RARE DISEASE
Hereditary spastic paraplegia
Hereditary spastic paraplegia
Hereditary spastic paraplegia
Synonyms: Familial spastic paraplegia, HSP, Hereditary spastic paraparesis, SPG, Strümpell-Lorrain disease
Synonyms: Familial spastic paraplegia, HSP, Hereditary spastic paraparesis, SPG, Strümpell-Lorrain disease
Synonyms: Familial spastic paraplegia, HSP, Hereditary spastic paraparesis, SPG, Strümpell-Lorrain disease
Drug discovery
3
drugs
With orphan designations
Overview
Hereditary Spastic Paraplegia (HSP) is a group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness due to corticospinal tract degeneration. Classified as pure (focused on motor symptoms) or complex (with additional neurological/Systemic features like ataxia, cognitive impairment, or neuropathy), HSP is diagnosed through clinical evaluation, exclusion of mimics, and genetic testing. While no disease-modifying therapies exist, management includes spasticity-reducing medications (e.g., baclofen, botulinum toxin), physical therapy, and assistive devices. Progression varies, with some requiring wheelchairs, but life expectancy is typically unaffected in pure forms [1][2][6][12].
Burden
Progressive mobility loss often necessitates assistive devices (20–40% require wheelchairs). Complications include urinary dysfunction, chronic pain, and comorbidities like depression (19%), psoriasis, and gastrointestinal issues. Complex HSP increases caregiver dependency and reduces quality of life [1][9][11].
Therapies
Pharmacological: Muscle relaxants (oral/intrathecal baclofen, tizanidine), botulinum toxin injections, gabapentin [2][3][6].
Non-pharmacological: Physical therapy (stretching, gait training), orthotics, and surgical interventions (selective dorsal rhizotomy) [3][6][13].
Emerging targets: Rapamycin, N-acetyl cysteine, and PCSK9 inhibitors in preclinical/clinical trials [8][13][18].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
600 drug discovery papers about Hereditary spastic paraplegia, with 6 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
600 drug discovery papers about Hereditary spastic paraplegia, with 6 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-29 | Serine palmitoyltransferase (SPT) inhibition in SPTSSA-related complex hereditary spastic paraplegia.
Defective feedback inhibition of serine palmitoyltransferase (SPT) caused by pathogenic SPTSSA variants underlies childhood-onset complex hereditary spastic paraplegia, yet the developmental timing and therapeutic reversibility of sphingolipid dysregulation remain unclear. We generated a knock-in mouse carrying the disease-associated SptssaT51I variant and show that heterozygous animals exhibit preserved intrinsic SPT activity but impaired ORMDL-mediated regulation, leading to sustained elevation of bioactive sphingolipid intermediates that peak during postnatal myelination. Although gross myelin formation was initially maintained, excess sphingolipid flux rendered oligodendrocytes and neurons selectively vulnerable. Dietary L-serine, which augments SPT substrate availability, amplified sphingolipid accumulation in mutant but not wild-type mice, unmasking progressive spasticity, axonal injury, myelin ultrastructural defects, and, when administered during early postnatal development, severe pulmonary pathology likely responsible for lethality. Pharmacologic SPT inhibition with myriocin normalized sphingolipid synthesis, prevented serine-induced lethality, and reversed neurological and metabolic abnormalities. Translating these findings, treatment of a child with SPTSSA-T51I-associated complex hereditary spastic paraplegia using the FDA approved SPT inhibitor D-Cycloserine resulted in sustained improvement in spasticity, reduced baclofen requirement, and decreased plasma levels of neurofilament light chain (NFL). These data define dysregulated sphingolipid biosynthesis as a developmentally and metabolically sensitive driver of neurodegeneration and suggest SPT inhibition as a mechanistically grounded therapeutic strategy.
2026-09-28 | A rare case of hereditary spastic paraplegia with homozygous mutation in the ZFYVE26 gene.
Hereditary spastic paraplegia (HSP) refers to a group of rare, progressive neurodegenerative disorders characterized by spasticity and weakness predominantly affecting the lower limbs, with significant clinical and genetic heterogeneity. Clinically, HSP is classified into "pure" and "complicated" forms. SPG15 (ZFYVE26) is a rare autosomal recessive subtype typically presenting in childhood with cognitive decline, followed by the development of gait disturbances and spasticity, often accompanied by thinning of the corpus callosum. Here, we report the case of a 19-year-old female patient, born to consanguineous parents, presenting with gait disturbance, lower limb spasticity, and dysarthria. Neurological examination revealed motor and mental retardation, bilateral lower limb spasticity, increased deep tendon reflexes, thinning of the corpus callosum on brain MRI, white matter hyperintensities, and the characteristic "lynx ear sign". Electromyography demonstrated marked sensorimotor demyelinating polyneuropathy in the lower limbs and evidence of anterior horn cell involvement. Genetic analysis, prompted by clinical and radiological findings, revealed a homozygous mutation in exon 19 of the ZFYVE26 gene: c.3382C>T p.Q1128*.
2026-09-19 | Defective ATP13A2-ITCH-ALIX signaling impairs intraluminal vesicle biogenesis and increases neuronal vulnerability.
ATP13A2 is a lysosomal P5B-type ATPase whose loss-of-function mutations are associated with a spectrum of neurodegenerative disorders, including early-onset Parkinson's disease, Kufor-Rakeb syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. Although ATP13A2 is known to contribute to lysosomal homeostasis and, thereby, to neuronal degeneration, emerging evidence suggests that it may also influence exosome biology. However, the mechanisms by which endogenous ATP13A2 regulates exosome biogenesis and the relevance of this process to neuronal vulnerability remain unclear. In the present study, using multiple ATP13A2-deficient human cell models, we demonstrated that ATP13A2 deficiency impairs intraluminal vesicle (ILV) biogenesis and reduces exosome secretion across diverse cellular contexts. Loss of ATP13A2 did not markedly affect endocytosis, early endosome abundance, or multivesicular body formation, but it consistently reduced ILV density within multivesicular bodies. Mechanistically, ATP13A2 deficiency promoted lysosome-associated accumulation of the E3 ubiquitin ligase ITCH, which enhanced ubiquitin-proteasome-dependent degradation of ALG-2-interacting protein X (ALIX), a critical adaptor of the endosomal sorting complex required for transport machinery that mediates ILV membrane remodeling. Restoration of ALIX expression or reduction of Itchy E3 ubiquitin-protein ligase (ITCH) activity rescued the ILV biogenesis defects in ATP13A2-deficient neuronal cells. Furthermore, dysregulation of the ATP13A2-ITCH-ALIX pathway increased neuronal susceptibility to mitochondrial stress, whereas restoration of ALIX or reduction of ITCH activity markedly improved neuronal survival. Together, these results identify an ATP13A2-ITCH-ALIX signaling axis linking lysosomal dysfunction to impaired ILV biogenesis and exosome regulation. Our study suggests that defective ILV biogenesis contributes to neuronal vulnerability and that modulation of the ATP13A2-ITCH-ALIX pathway may represent a therapeutic strategy for ATP13A2-associated neurodegeneration.
2026-09-06 | Cognitive impairment as a manifestation of SPG7: case report.
Hereditary spastic paraplegia (HSP) is a group of genetic disorders caused by >80 genes that can be described as either pure or complex forms.We report a case of a patient with a complex form of SPG7 with significant cognitive impairment.A 42-year-old man presented with a 10-year history of dysarthria, 5 years of gait difficulties, and 3 years of cognitive symptoms. Neuropsychological analysis showed deficits involving speed of information processing, mental flexibility, ideational fluency, verbal concept formation, visual working memory, and visual-spatial perception. Next-generation sequencing on whole blood revealed 2 heterozygous pathogenic variants in SPG7 (c. 1049_1077del, p. Pro350Glnfs*36 and c. 1529C>T, p. Ala510Val).There are emerging reports of complex forms of SPG7 presenting with impairments in memory, executive dysfunction, language, visuospatial processing, social functioning, and emotional communication. In this report, we describe a complex SPG7 patient who underwent formal neuropsychological testing to assess cognitive status in depth. This revealed deficits in speed of processing, visuospatial working memory and perception, impaired non-verbal intellect, and overall lack of insight, which have not yet been described in the literature.
2026-08-31 | A glucosylcholesterol-cytoskeleton axis links GBA2 loss-of-function to synaptic and mitochondrial pathology in Hereditary Spastic Paraplegia
Abstract Background GBA2-associated hereditary spastic paraplegia (SPG46) is a rare autosomal recessive neurodegenerative disorder caused by loss-of-function mutations in GBA2 , encoding the non-lysosomal glucocerebrosidase 2. GBA2 deficiency leads to glucosylceramide (GlcCer) accumulation and glucosylated cholesterol (GlcChol) depletion, causing cytoskeletal defects in immature neurons. However, the mechanisms linking lipid dysregulation to neuronal dysfunction remain poorly understood. Methods We modelled GBA2 loss of function by chronic pharmacological inhibition in mouse cerebellar granule neurons (CGNs) and assessed neuronal morphology, synaptic organization, Ca 2+ dynamics, mitochondrial function and actin cytoskeleton during maturation. Proteomic profiling was performed in GBA2-inhibited and GlcChol-supplemented neurons. Findings were validated in a zebrafish gba2 crispant model by evaluating motor behavior, cerebellar development, neuronal organization and mitochondrial function, and in patient-derived fibroblasts carrying a homozygous pathogenic GBA2 variant (NM_020944). The role of RAC1 was studied in both neurons and patients’ cultured skin fibroblasts, and upon rac1 pharmacological inhibition in zebrafish crispants. Results Chronic GBA2 inhibition impaired axonal outgrowth in immature CGNs but not neurite complexity in mature neurons, suggesting morphological compensation. Nevertheless, mature neurons displayed enlarged presynaptic terminals, impaired synaptic vesicle clustering and altered Ca 2+ responses to potassium and glutamate, the latter associated with NMDA receptor redistribution without changes in total receptor levels. Mitochondrial alterations were observed in CGNs, patient fibroblasts and zebrafish, consistent with defective architecture of the mitochondrial network. Proteomics revealed convergent alterations in actin cytoskeleton, synaptic pathways and cellular metabolism following both GBA2 inhibition and GlcChol supplementation. GlcChol bidirectionally regulated RAC1 function, likely altering its spatial distribution rather than its global activation. Confocal imaging confirmed abnormal RAC1 and F-actin localization in patient fibroblasts. Zebrafish gba2 crispants recapitulated motor deficits, Purkinje cell loss, motor neuron disorganization and mitochondrial abnormalities. Pharmacological Rac1 inhibition rescued motor behavior and neuronal organization, linking cytoskeletal disorganization to the observed phenotype in the zebrafish model. Conclusions Our findings identify a pathogenic GlcChol-RAC1-actin signalling axis linking lipid imbalance to synaptic disorganization, NMDA receptor redistribution and mitochondrial dysfunction in SPG46. The selective vulnerability of corticospinal neurons, cerebellar granule neurons and Purkinje cells may reflect their dependence on this pathway. Rac1 inhibition rescues disease phenotypes in vivo , highlighting this pathway as a promising therapeutic target.
proteins
2026-06-04 | LASER couples damage sensing to ESCRT assembly for lysosome repair.
Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of endosomal sorting complex required for transport (ESCRT) I-III rapidly counteracts membrane damage, but it is unclear how ESCRT-I recognizes defective lysosomal membranes. Here, leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we identified LC3/GABARAP-assisted stimulator for ESCRT recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes and couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is TFG, an endoplasmic reticulum exit-site-resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3 and GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit TSG101 via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT-I-II-III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.
2026-02-21 | Structural analysis of the plant glycoside hydrolase family 116 glucosylceramidase AtGCD3 by cryogenic electron microscopy.
Glucosylceramide (GlcCer) is a common glycosphingolipid that accumulates in cells in response to Gaucher disease, diabetes, and skin disorders in humans and is also found in plants. In animals, GlcCer is catabolized by glucosylcerebrosidase 1 and 2 (GBA1 and GBA2). GBA1 is a lysosomal enzyme in glycoside hydrolase (GH) family GH30, while GBA2 is a membrane-associated cytoplasmic protein in family GH116. Currently, there are no experimental structures of eukaryotic GH116 homologues. Although the bacterial TxGH116 β-glucosidase structure was determined by X-ray crystallography, TxGH116 does not hydrolyze glucosylceramides, unlike the animal and plant enzymes. Therefore, we have investigated the structure of plant GH116 (AtGCD3) by cryogenic electron microscopy (Cryo-EM) single-particle analysis. The recombinant AtGCD3 protein was produced in Escherichia coli and purified by immobilized-metal affinity chromatography followed by size-exclusion chromatography. The Cryo-EM structure revealed a unique hexameric arrangement, composed of a dimer of trimers. Hydrophobic interactions and hydrogen bonds stabilize each trimer at the trimer interface. The two trimers stack face-to-face with a slight twist, with salt bridges and hydrogen bonding at their interface. Two α-helices not found in previously described GH116 structures cover the active site, forming two hydrophobic channels that may be involved in glucosylceramide binding. Molecular dynamics simulations showed that glucosylceramide can bind stably in the active site with its lipid tails in these channels. This first eukaryotic structure of a GH116 enzyme generates a template for improved modeling of human GBA2, with implications for treating human diseases, such as Gaucher disease and hereditary spastic paraplegia.
2025-11-27 | Swiss Cheese Gene Is Important for Intestinal Barrier, Microbiome, and Lipid Metabolism Regulation in Drosophila Gut.
Mutations in the human patatin-like lysophospholipase domain containing the 6 gene PNPLA6 encode an evolutionarily conserved (lyso)phospholipase, leading to the development of a complex hereditary spastic paraplegia 39 (SPG 39) and a number of rare severe syndromes in humans. Diseases disrupt the functioning of the nervous and reproductive systems and the gastrointestinal tract. The study aims to investigate the role of the Drosophila melanogaster swiss cheese gene, an ortholog of the human PNPLA6 gene, in gut function. We showed that the swiss cheese gene knockout leads to changes in the morphology of the midgut, disruption of the septate junction structure and the intestinal barrier permeability, and a decrease in the lipid droplet number in enterocytes. As a result of such disturbances, intestinal stem cells (ISCs) proliferation is activated, and the gut microbiome is altered. Ectopic expression of human PNPLA6 leads to the recovery of the intestinal barrier in the fly gut. The example of Drosophila demonstrates the important role of evolutionarily conserved (lyso)phospholipase in intestinal homeostasis.
2025-11-06 | Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.
Hereditary Spastic Paraplegias (HSPs) are a group of heterogeneous neurological diseases characterized by axonal degeneration of corticospinal motor neurons. SPG15, a common autosomal recessive form of HSP, is caused by mutations in the ZFYVE26 gene that encodes the spastizin protein. Spastizin partially localizes to mitochondria, suggesting a potential role in mitochondrial function. To investigate this possibility and explore treatments to mitigate neurodegeneration caused by spastizin deficiency, SPG15 patient-specific induced pluripotent stem cells (iPSCs) were generated from patient fibroblasts and differentiated into cortical projection neurons. The SPG15 iPSC-derived neurons exhibited reduced ATP production compared to control neurons, indicating mitochondrial dysfunction in spastizin-deficient neurons. Also, given increased fragmentation of mitochondria in SPG15 neurons, we examined whether restoring mitochondrial morphology dynamics using P110, a peptide inhibitor of the mitochondrial fission protein DRP1, could protect SPG15 neurons. Indeed, treatment with P110 significantly suppressed the accumulated axonal swellings in SPG15 neurons. Further examination of the underlying mechanisms revealed that P110 restored mitochondrial morphology, ameliorated mitochondrial oxidative stress, and improved mitochondrial health, but it did not affect necrosis-related membrane integrity, suggesting specific targeting of mitochondrial deficits by P110. Furthermore, P110 significantly mitigated disease-related apoptosis in SPG15 neurons. Collectively, these findings reveal that restoring mitochondrial morphology and function using P110 lessens mitochondrial oxidative stress and mitigates degeneration of SPG15 neurons, offering a novel therapeutic approach for SPG15.
2025-10-28 | Botulinum Toxin Treatment in Hereditary Spastic Paraplegia-A Comprehensive Review and Update.
Using Medline and Scopus as search engines, we identified reports of 10 clinical studies (published up to 1 September 2025) on botulinum neurotoxin therapy for hereditary spastic paraplegia (HSP). Nine studies were conducted in adults and one in children. Only one of the ten studies was double-blind and placebo-controlled. The search strategy included only articles published in English and articles providing basic information such as the type of the study, type and dose of the toxin and results of the treatment. Articles not in English, case reports and review articles were excluded. A total of 258 patients were included across all studies. The injected toxin in the open-label studies was botulinumtoxin-A (Botox or Dysport or Xeomin), whereas in the blinded study, the investigators used Prosigne. All open-label studies, which used FDA approved botulinumtoxin-A neurotoxins, demonstrated a degree of motor and non-motor improvement, whereas treatment with Prosigne did not improve patients' function. The possible reasons for this discrepancy between the blinded study and the open-label studies are discussed. We found no studies on the effect of BoNTs on bladder dysfunction in HSP. There is a need for double-blind, placebo-controlled studies assessing the efficacy of FDA-approved botulinum neurotoxins in children and adults affected by hereditary spastic paraparesis. Such studies should also investigate the effect(s) of early botulinum neurotoxin therapy in this disorder. The novelty of this review is that it represents a comprehensive and critical literature review on this subject, with no other studies of this kind published previously. It also includes data not present in previous reviews of this subject.
gene therapies
2026-09-21 | Phenotypic Spectrum and Clinical Approach to Early-Onset Hereditary Spastic Paraplegia.
Early-onset hereditary spastic paraplegias (HSPs) are an underrecognized cause of progressive spasticity, gait impairment, and movement disorders in children and young adults. HSPs frequently mimic cerebral palsy or genetic, metabolic, and acquired disorders, resulting in diagnostic delay. Their broad phenotypic spectrum, encompassing dystonia, parkinsonism, and neurodevelopmental features, makes them highly relevant to movement disorder practitioners across the lifespan. This review summarizes the phenotypic spectrum of early-onset HSP, outlines a practical diagnostic approach for clinicians, and discusses therapeutic strategies. We conducted a narrative review of PubMed-indexed literature through February 2026, supplemented by expert consensus. HSPs typically presenting in childhood and adolescence, inclusive of forms presenting across a broader age spectrum, with attention to subtypes presenting with movement disorders, were considered. Early-onset HSPs encompass both pure and complex forms, with SPG4 (SPAST) and SPG11 (SPG11/KIAA1840) among the most prevalent etiologies. Diagnostic challenges include distinction from cerebral palsy and other movement disorders including dopa-responsive dystonia, and identification of neuroimaging signatures in specific subtypes. A multidisciplinary management approach remains central, with spasticity, movement disorder, and neurological comorbidities each requiring targeted consideration. Disease-modifying therapies are emerging, including gene replacement strategies and antisense oligonucleotide approaches for select subtypes. Early-onset HSPs represent a clinically and genetically heterogeneous group with substantial overlap with movement disorder practice. Awareness of characteristic phenotypes, early genetic testing, and an individualized multidisciplinary approach are essential. Recent advances in natural history characterization and mechanism-targeted therapeutics signal a transition toward disease-modifying treatment strategies and offer cautious optimism for affected individuals.
2026-06-09 | When to Question Cerebral Palsy: Hereditary Spastic Paraplegia Masquerading as Cerebral Palsy (P4-8.006)
To describe a case of progressive lower-extremity weakness initially attributed to CP and subsequently reclassified as HSP following genetic testing.
2026-02-27 | A GJA1 Variant Triggers Earlier SPG4 Onset by Destabilizing Deubiquitinase VCPIP1 to Lower SPASTIN Levels.
SPG4, the most common hereditary spastic paraplegia caused by SPAST variants, exhibits extreme age-at-onset variability, indicative of uncharacterized genetic modifiers. The GJA1R148Q variant (linked to oculodentodigital dysplasia) may modulate SPG4 pathogenesis, yet its underlying molecular mechanism remains undefined. We investigated the molecular mechanism by which GJA1R148Q accelerates early SPG4 onset in a proband with dual SPAST and GJA1 variants, and validated its function as a disease modifier for SPG4. We performed comprehensive clinical phenotyping, segregation analysis, coimmunoprecipitation, ubiquitination analyses, CRISPR-mediated correction in patient induced pluripotent stem cell2013derived organoids, and a targeted deubiquitinase screen. The GJA1R148Q enhanced the physical interaction between SPASTIN and GJA1, accelerated the degradation of deubiquitinase valosin-containing protein interacting protein 1 (VCPIP1), and thereby reduced SPASTIN levels. CRISPR-based reversion of the R148Q restored SPASTIN levels and rescued microtubule-severing function. Notably, maternal relatives carrying the GJA1R148Q allele alone exhibited no neurological abnormalities. The GJA1R148Q variant, although non-neurological in isolation, acts as a disease modifier that precipitates SPG4 by exacerbating SPASTIN haploinsufficiency through destabilization of VCPIP1, positioning GJA1-VCPIP1-SPASTIN signaling as a potential therapeutic axis for SPG4 treatment. © 2026 International Parkinson and Movement Disorder Society.
2026-01-19 | Association of spinal cord structure with cognition in hereditary spastic paraplegia type 5.
Cognitive deficits often accompany brain structural changes, but the association between spinal cord atrophy and cognitive function remains unclear. Spastic paraplegia type 5 (SPG5) is a subtype of hereditary spastic paraplegias (HSPs), caused by mutations in cholesterol metabolism genes, with radiological features of spinal cord atrophy. Our study aims to explore cognitive impairment in SPG5 and its relation to spinal cord structure. We conducted a prospective cross-sectional study with 30 HSPs patients and 47 healthy controls (HC), performing brain and spinal cord MRI and neuropsychological assessments. We investigated correlations between cognitive performance and MRI measurements. Compared to HC, SPG5 patients exhibited significant impairments in the Benton Judgment of Line Orientation Test (p = 0.033), Controlled Oral Word Association Test (p = 0.028), and Symbol Digit Modalities Test (p = 0.023). SPG5 patients also demonstrated significant reductions in spinal cord and thoracic cord cross-sectional area (CSA), anterior-posterior (AP) diameter, and right-left (RL) total (All p < 0.01). Specifically, the thoracic cord RL total was positively correlated with scores on the Brief Visuospatial Memory Test - Revisited delayed recall (BVMT-R DR) and Montreal Cognitive Assessment (MoCA). The spinal cord RL total explained 81% of the variance in BVMT-R DR (p = 0.015) and 74% of the variance in MoCA (p = 0.027). SPG5 patients demonstrate deficits in visuospatial perception, executive function, and information processing speed. Thoracic spinal cord RL total was positively associated with visual memory and global cognition.
2025-11-28 | Intracerebroventricular SPAST-AAV9 gene therapy prevents manifestation of symptoms in a mouse model of SPG4 hereditary spastic paraplegia.
Hereditary spastic paraplegia type 4 is characterized by gait impairments, progressive spasticity, and weakness of the lower limbs, resulting from degeneration of the corticospinal tracts. The disease is caused by mutations of the SPAST gene, which encodes a major isoform of spastin called M87 and a minor isoform called M1. Owing to its N-terminal hydrophobic domain not shared by M87, M1 is the isoform that becomes toxic when mutated. Loss of function of either M1 or M87 or both may also play a role in the disease, sensitizing corticospinal motor neurons to the toxicity of mutant M1. Here, we pursued silence-and-replace gene therapy, which addresses both gain-of-toxicity and loss-of-function components of the disease. We generated an adeno-associated serotype 9 viral vector containing microRNA to stop the expression from the endogenous SPAST gene and cDNA to express healthy human M1 and M87. The vector was introduced by intracerebroventricular injections into newborn pups of SPAST-C448Y, a mouse model of the disease that expresses human mutant spastin and displays adult-onset corticospinal degeneration and gait defects. The treatment successfully replaced both isoforms of endogenous spastin with healthy spastin at physiological levels, and prevented the onset and progression of corticospinal degeneration and gait defects.
oligonucleotides
2025-08-14 | Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.
Motor Neuron Diseases (MNDs) such as Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Hereditary Spastic Paraplegia (HSP), Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1), Multisystem Proteinopathy (MSP), Spinal and Bulbar Muscular Atrophy (SBMA), and ALS associated to Frontotemporal Dementia (ALS-FTD), have traditionally been studied as distinct entities, each one with unique genetic and clinical characteristics. However, emerging research reveals that these seemingly disparate conditions converge on shared molecular mechanisms that drive progressive neuroaxonal degeneration. This narrative review addresses a critical gap in the field by synthesizing the most recent findings into a comprehensive, cross-disease mechanisms framework. By integrating insights into RNA dysregulation, protein misfolding, mitochondrial dysfunction, DNA damage, kinase signaling, axonal transport failure, and immune activation, we highlight how these converging pathways create a common pathogenic landscape across MNDs. Importantly, this perspective not only reframes MNDs as interconnected neurodegenerative models but also identifies shared therapeutic targets and emerging strategies, including antisense oligonucleotides, autophagy modulators, kinase inhibitors, and immunotherapies that transcend individual disease boundaries. The diagnostic and prognostic potential of Neurofilament Light Chain (NfL) biomarkers is also emphasized. By shifting focus from gene-specific to mechanism-based approaches, this paper offers a much-needed roadmap for advancing both research and clinical management in MNDs, paving the way for cross-disease therapeutic innovations.
2023-08-04 | Strumpellin/WASHC5 regulates the structural plasticity of cortical neurons involved in gait coordination.
Strumpellin/Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex subunit 5 (WASHC5) is a core component of the WASH complex, and its mutations confer pathogenicity for hereditary spastic paraplegia (HSP) type SPG8, a rare neurodegenerative gait disorder. WASH complex activates actin-related protein-2/3-mediated actin polymerization and plays a pivotal role in intracellular membrane trafficking in endosomes. In this study, we examined the role of strumpellin in the regulation of structural plasticity of cortical neurons involved in gait coordination. Administration of a lentivirus containing a strumpellin-targeting short hairpin RNA (shRNA) to cortical motor neurons lead to abnormal motor coordination in mice. Strumpellin knockdown using shRNA attenuated dendritic arborization and synapse formation in cultured cortical neurons, and this effect was rescued by wild-type strumpellin expression. Compared with the wild-type, strumpellin mutants N471D or V626F identified in patients with SPG8 exhibited no differences in rescuing the defects. Moreover, the number of F-actin clusters in neuronal dendrites was decreased by strumpellin knockdown and rescued by strumpellin expression. In conclusion, our results indicate that strumpellin regulates the structural plasticity of cortical neurons via actin polymerization.
2022-05-03 | Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4.
While the anticipated rise of disease-modifying therapies calls for reliable trial outcome parameters, fluid biomarkers are lacking in spastic paraplegia type 4 (SPG4), the most prevalent form of hereditary spastic paraplegia. We therefore investigated serum neurofilament light chain (sNfL) as a potential therapy response, diagnostic, monitoring, and prognostic biomarker in SPG4. We assessed sNfL levels in 93 patients with SPG4 and 60 healthy controls. The longitudinal study of sNfL levels in SPG4 patients covered a baseline, 1-year follow-up and 2-year follow-up visit. Levels of sNfL were significantly increased in patients with genetically confirmed SPG4 compared to healthy controls matched in age and sex (p = 0.013, r = 0.2). Our cross-sectional analysis revealed a greater difference in sNfL levels between patients and controls in younger ages with decreasing fold change of patient sNfL elevation at older ages. Over our observational period of 2 years, sNfL levels remained stable in SPG4 patients. Disease severity and progression did not correlate with sNfL levels. Our longitudinal data indicate a stable turnover of sNfL in manifest SPG4; therefore, sNfL levels are not suitable to monitor disease progression in SPG4. However, sNfL may be valuable as a therapy response biomarker, since its turnover could be modified by interventions. As the course of sNfL levels appears to be most dynamic around the onset of SPG4, the ability to detect a therapy response appears to be especially promising in younger patients, matching the need to initiate treatment in early disease stages.
2020-09-04 | Suppression of spastin Mutant Phenotypes by Pak3 Loss Implicates a Role for Reactive Glia in AD-HSP
Neurodegenerative mechanisms due to mutations in spastin currently center on neuronal defects, primarily in microtubule and endomembrane regulation. Spastin loss in Drosophila larvae compromises neuronal microtubule distribution, alters synaptic bouton morphology, and weakens synaptic transmission at glutamatergic neuromuscular junction (NMJ) synapses. Pak3, a p21-activated kinase that promotes actin polymerization and filopodial projections, is required for these spastin mutant defects; animals lacking both genes have normal NMJs. Here we show that Pak3 is expressed in central and peripheral glial populations, and reduction of Pak3 specifically in subperineurial glial cells is sufficient to suppress the phenotypes associated with spastin loss. Subperineurial glia in the periphery ensheathe motor neuron axons and have been shown to extend actin-based projections that regulate synaptic terminals during normal NMJ development. We find that these subperineurial glial projections are Pak3-dependent and nearly twice as frequent in spastin mutants, while in Pak3, spastin double mutants, neither glial projections nor synaptic defects are observed. Spastin deficiency thus increases Pak3-dependent subperineurial glia activity, which is in turn required for neuronal defects. Our results demonstrate a central role for Pak3-mediated, altered glial behavior in the neuronal defects due to spastin loss, and suggest that a similar reactive glia-mediated mechanism may underlie human AD-HSP pathogenesis.
2019-12-06 | MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons.
Recent reports, including ours, have indicated that microRNA (miR)-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a potential therapeutic target for the treatment of atherosclerosis. Here, we show that SPAST, which encodes a microtubule-severing protein called SPASTIN, was a novel target gene of miR-33 in human. Actually, the miR-33 binding site in the SPAST 3'-UTR is conserved not in mice but in mid to large mammals, and it is impossible to clarify the role of miR-33 on SPAST in mice. We demonstrated that inhibition of miR-33a, a major form of miR-33 in human neurons, via locked nucleic acid (LNA)-anti-miR ameliorated the pathological phenotype in hereditary spastic paraplegia (HSP)-SPG4 patient induced pluripotent stem cell (iPSC)-derived cortical neurons. Thus, miR-33a can be a potential therapeutic target for the treatment of HSP-SPG4.
other
2026-09-03 | Validation of a Cellular Imaging-Based Method as a Potential Biomarker for SPG4 Hereditary Spastic Paraplegia.
Hereditary Spastic Paraplegia (HSP) comprises a group of rare genetic diseases characterized by length-dependent axonal degeneration of the corticospinal tracts and dorsal columns, whose main clinical feature is spastic gait. Pathogenic variants in the SPG4 gene cause Spastic Paraplegia Type 4 (SPG4-HSP), the most common form of HSP. SPG4/SPAST encodes spastin, a protein involved in microtubule regulation and lipid droplet behavior. SPG4-HSP shows extreme heterogeneity in both clinical manifestations and genetics. Although no cure is currently available, several strategies aimed at restoring spastin levels are emerging; however, SPG4-HSP still lacks accessible cellular readouts for clinical studies. This study evaluates a cell-imaging approach that quantifies the distance between nucleus and cell centroid (dcnc) in peripheral blood mononuclear cells (PBMCs) in a genetically and clinically heterogeneous SPG4-HSP cohort. PBMCs from 48 molecularly confirmed SPG4-HSP patients and 21 healthy controls (HC) were analyzed by automated cell imaging. Dcnc and additional cytoskeletal and lipid droplet-related parameters were measured. Patient-level discrimination was assessed via cross-validated classification; correlations with molecular and clinical features were explored. At the patient level, dcnc distinguishes SPG4-HSP from HC, independently of mutation type and disease severity, supporting robust cross-validated classification and inverse correlation with spastin protein levels. Dcnc is a robust, non-invasive, and mutation-independent cellular candidate biomarker for SPG4-HSP. It also offers preliminary evidence consistent with spastin target engagement supporting evaluation in future clinical trials.
2025-10-03 | Development of a Human iPSC-Derived "Corticospinal Tract-on-a-Chip" for Neurodegenerative Disease Research.
Degeneration of the corticospinal tract is a central feature in a number of neurodegenerative disorders and leads to significant disability. However, modeling corticospinal neuron (CSN) pathology and corticospinal connectivity in neurological disorders is particularly challenging. While rodent models are important for understanding early degeneration of CSN, interspecies differences in corticospinal connectivity and challenges of in vivo study suggest that human in vitro models of corticospinal biology may be ripe for development. Human induced pluripotent stem cells (hiPSC) are promising tools for overcoming intrinsic limitations that arise from physiological differences between rodents and humans. We have developed an innovative hiPSC-based microfluidic platform for modeling human CSN and spinal motor neuron (SpMN) connectivity. The incorporation of regionally specific astrocyte subtypes (cortical and spinal) in addition to CSNs and SpMNs in this newly designed system allows for the modeling of both regional and neural cell-subtype interactions. Using this model, multielectrode array electrophysiology reveals the maturation of both cortical and spinal motor neurons over the time course of 12 weeks. Retrograde labeling methods demonstrate synaptic connectivity between corticospinal and spinal motor neurons. Optogenetic strategies to selectively activate excitatory CNs attenuated by glutamate receptor antagonism confirms the functional relevance of the model. Incorporating morphological, electrophysiological and physiological measures of corticospinal connectivity, this platform is a versatile model for use in neurodegenerative disease research and for the future development of targeted CSN therapies. Degeneration of the corticospinal tract is a key feature of numerous neurodegenerative diseases, yet current in vitro models lack the anatomical and functional fidelity to study this system. We developed a human iPSC-derived "Corticospinal Tract-on-a-Chip" using a multielectrode array platform that incorporates regionally patterned cortical and spinal neurons and astrocytes. This model demonstrates structural and functional synaptic connectivity and enables longitudinal electrophysiological recordings. Critically, it supports compartment-specific manipulation and real-time analysis of CST network dynamics, capabilities lacking in existing systems. By mimicking human corticospinal physiology in vitro , this platform offers a novel tool for mechanistic investigation and preclinical testing of CST-targeted therapies. It holds broad relevance for studying disorders such as ALS, hereditary spastic paraplegia, and primary lateral sclerosis.
2025-03-18 | Toxoplasmosis accelerates the progression of hereditary spastic paraplegia.
The parasitic protozoa Toxoplasma gondii chronically infects the central nervous system of an estimated one-third of the human population. Infection is generally subclinical, but immunocompromised individuals can experience a variety of neurological symptoms. Meta-analyses of T. gondii seropositivity have suggested a correlation between T. gondii infection and neurologic disease. Although mechanistic studies on the relationship between T. gondii infection and neurologic disease have been attempted in mice, they are particularly susceptible to T. gondii, making them an effective model for investigating mechanisms of infection, but not ideal for examining the relationship between long-term chronic T. gondii infection and neurologic disease. Rats more closely mimic human T. gondii cyst levels after acute infection, but a lack of rat models for neurologic disease has limited studies on the interplay between T. gondii infection and neurologic disease progression. We have employed a previously characterized rat model of a complex form of hereditary spastic paraplegia (HSP), a class of neurodegenerative disorders that cause axonal degeneration and lower limb spasticity, in order to assess the effect of chronic T. gondii infection on neurodegenerative disease. We find that infected rats with hereditary spastic paraplegia exhibit significantly exacerbated behavioral and neuromorphological HSP symptoms compared with uninfected HSP mutant rats, with little correlative effect in infected versus uninfected control animals. We further find that all infected rats, regardless of genotype, exhibit a robust immune response to T. gondii infection, presenting with parasite levels below the limit of detection of multiple assays of parasitemia and exhibiting no detectable increase in neuroinflammation 7 weeks post-infection. These results suggest that chronic undetected T. gondii infection may exacerbate neurodegenerative disease even in immunocompetent individuals and may contribute to neurodegenerative disease heterogeneity.IMPORTANCEThe long-term consequences of previous acute infections are poorly understood but are becoming increasingly appreciated, particularly in the era of long COVID. Altered progression of other diseases later in life may be among the long-term consequences of previous infections. Here, we investigate the relationship between previous infections with the parasite Toxoplasma gondii, which infects ~30% of the global population, and neurodegenerative disease using a rat model of hereditary spastic paraplegia (HSP). We find that previous infections with T. gondii accelerate motor dysfunction in HSP rats, despite robust clearance of the parasite by infected rats. Our results suggest that previously cleared infections may alter the progression of other diseases later in life and contribute to neurodegenerative disease heterogeneity.
2024-03-14 | Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.
Hereditary spastic paraplegias (HSPs) comprise a family of degenerative diseases mostly hitting descending axons of corticospinal neurons. Depending on the gene and mutation involved, the disease could present as a pure form with limb spasticity, or a complex form associated with cerebellar and/or cortical signs such as ataxia, dysarthria, epilepsy, and intellectual disability. The progressive nature of HSPs invariably leads patients to require walking canes or wheelchairs over time. Despite several attempts to ameliorate the life quality of patients that have been tested, current therapeutical approaches are just symptomatic, as no cure is available. Progress in research in the last two decades has identified a vast number of genes involved in HSP etiology, using cellular and animal models generated on purpose. Although unanimously considered invaluable tools for basic research, those systems are rarely predictive for the establishment of a therapeutic approach. The advent of induced pluripotent stem (iPS) cells allowed instead the direct study of morphological and molecular properties of the patient's affected neurons generated upon in vitro differentiation. In this review, we revisited all the present literature recently published regarding the use of iPS cells to differentiate HSP patient-specific neurons. Most studies have defined patient-derived neurons as a reliable model to faithfully mimic HSP in vitro, discovering original findings through immunological and -omics approaches, and providing a platform to screen novel or repurposed drugs. Thereby, one of the biggest hopes of current HSP research regards the use of patient-derived iPS cells to expand basic knowledge on the disease, while simultaneously establishing new therapeutic treatments for both generalized and personalized approaches in daily medical practice.
2021-11-25 | Generation of induced pluripotent stem cell line (ZZUi030-A) from a patient with spastic paraplegia type 7.
Spastic paraplegia type 7 is a rare and classical monogenic inherited neurodegenerative disease caused by heterozygous mutations in the SPG7 gene. The principle clinical features include progressive spasms of the lower limbs, scissor gait, and muscle weakness. The disease currently has no effective treatment. In this study, we obtained dermal fibroblasts from a patient, which were successfully transformed into induced pluripotent stem cells (iPSCs) by employing reprogramming plasmids expressing OCT3/4, SOX2, KLF4, LIN28, and L-MYC. Our method provides a resource for mechanism exploration, drug research, cell transplantation, and gene therapy.
small molecules
2026-09-29 | Serine palmitoyltransferase (SPT) inhibition in SPTSSA-related complex hereditary spastic paraplegia.
Defective feedback inhibition of serine palmitoyltransferase (SPT) caused by pathogenic SPTSSA variants underlies childhood-onset complex hereditary spastic paraplegia, yet the developmental timing and therapeutic reversibility of sphingolipid dysregulation remain unclear. We generated a knock-in mouse carrying the disease-associated SptssaT51I variant and show that heterozygous animals exhibit preserved intrinsic SPT activity but impaired ORMDL-mediated regulation, leading to sustained elevation of bioactive sphingolipid intermediates that peak during postnatal myelination. Although gross myelin formation was initially maintained, excess sphingolipid flux rendered oligodendrocytes and neurons selectively vulnerable. Dietary L-serine, which augments SPT substrate availability, amplified sphingolipid accumulation in mutant but not wild-type mice, unmasking progressive spasticity, axonal injury, myelin ultrastructural defects, and, when administered during early postnatal development, severe pulmonary pathology likely responsible for lethality. Pharmacologic SPT inhibition with myriocin normalized sphingolipid synthesis, prevented serine-induced lethality, and reversed neurological and metabolic abnormalities. Translating these findings, treatment of a child with SPTSSA-T51I-associated complex hereditary spastic paraplegia using the FDA approved SPT inhibitor D-Cycloserine resulted in sustained improvement in spasticity, reduced baclofen requirement, and decreased plasma levels of neurofilament light chain (NFL). These data define dysregulated sphingolipid biosynthesis as a developmentally and metabolically sensitive driver of neurodegeneration and suggest SPT inhibition as a mechanistically grounded therapeutic strategy.
2026-09-28 | A rare case of hereditary spastic paraplegia with homozygous mutation in the ZFYVE26 gene.
Hereditary spastic paraplegia (HSP) refers to a group of rare, progressive neurodegenerative disorders characterized by spasticity and weakness predominantly affecting the lower limbs, with significant clinical and genetic heterogeneity. Clinically, HSP is classified into "pure" and "complicated" forms. SPG15 (ZFYVE26) is a rare autosomal recessive subtype typically presenting in childhood with cognitive decline, followed by the development of gait disturbances and spasticity, often accompanied by thinning of the corpus callosum. Here, we report the case of a 19-year-old female patient, born to consanguineous parents, presenting with gait disturbance, lower limb spasticity, and dysarthria. Neurological examination revealed motor and mental retardation, bilateral lower limb spasticity, increased deep tendon reflexes, thinning of the corpus callosum on brain MRI, white matter hyperintensities, and the characteristic "lynx ear sign". Electromyography demonstrated marked sensorimotor demyelinating polyneuropathy in the lower limbs and evidence of anterior horn cell involvement. Genetic analysis, prompted by clinical and radiological findings, revealed a homozygous mutation in exon 19 of the ZFYVE26 gene: c.3382C>T p.Q1128*.
2026-09-19 | Defective ATP13A2-ITCH-ALIX signaling impairs intraluminal vesicle biogenesis and increases neuronal vulnerability.
ATP13A2 is a lysosomal P5B-type ATPase whose loss-of-function mutations are associated with a spectrum of neurodegenerative disorders, including early-onset Parkinson's disease, Kufor-Rakeb syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. Although ATP13A2 is known to contribute to lysosomal homeostasis and, thereby, to neuronal degeneration, emerging evidence suggests that it may also influence exosome biology. However, the mechanisms by which endogenous ATP13A2 regulates exosome biogenesis and the relevance of this process to neuronal vulnerability remain unclear. In the present study, using multiple ATP13A2-deficient human cell models, we demonstrated that ATP13A2 deficiency impairs intraluminal vesicle (ILV) biogenesis and reduces exosome secretion across diverse cellular contexts. Loss of ATP13A2 did not markedly affect endocytosis, early endosome abundance, or multivesicular body formation, but it consistently reduced ILV density within multivesicular bodies. Mechanistically, ATP13A2 deficiency promoted lysosome-associated accumulation of the E3 ubiquitin ligase ITCH, which enhanced ubiquitin-proteasome-dependent degradation of ALG-2-interacting protein X (ALIX), a critical adaptor of the endosomal sorting complex required for transport machinery that mediates ILV membrane remodeling. Restoration of ALIX expression or reduction of Itchy E3 ubiquitin-protein ligase (ITCH) activity rescued the ILV biogenesis defects in ATP13A2-deficient neuronal cells. Furthermore, dysregulation of the ATP13A2-ITCH-ALIX pathway increased neuronal susceptibility to mitochondrial stress, whereas restoration of ALIX or reduction of ITCH activity markedly improved neuronal survival. Together, these results identify an ATP13A2-ITCH-ALIX signaling axis linking lysosomal dysfunction to impaired ILV biogenesis and exosome regulation. Our study suggests that defective ILV biogenesis contributes to neuronal vulnerability and that modulation of the ATP13A2-ITCH-ALIX pathway may represent a therapeutic strategy for ATP13A2-associated neurodegeneration.
2026-09-06 | Cognitive impairment as a manifestation of SPG7: case report.
Hereditary spastic paraplegia (HSP) is a group of genetic disorders caused by >80 genes that can be described as either pure or complex forms.We report a case of a patient with a complex form of SPG7 with significant cognitive impairment.A 42-year-old man presented with a 10-year history of dysarthria, 5 years of gait difficulties, and 3 years of cognitive symptoms. Neuropsychological analysis showed deficits involving speed of information processing, mental flexibility, ideational fluency, verbal concept formation, visual working memory, and visual-spatial perception. Next-generation sequencing on whole blood revealed 2 heterozygous pathogenic variants in SPG7 (c. 1049_1077del, p. Pro350Glnfs*36 and c. 1529C>T, p. Ala510Val).There are emerging reports of complex forms of SPG7 presenting with impairments in memory, executive dysfunction, language, visuospatial processing, social functioning, and emotional communication. In this report, we describe a complex SPG7 patient who underwent formal neuropsychological testing to assess cognitive status in depth. This revealed deficits in speed of processing, visuospatial working memory and perception, impaired non-verbal intellect, and overall lack of insight, which have not yet been described in the literature.
2026-08-31 | A glucosylcholesterol-cytoskeleton axis links GBA2 loss-of-function to synaptic and mitochondrial pathology in Hereditary Spastic Paraplegia
Abstract Background GBA2-associated hereditary spastic paraplegia (SPG46) is a rare autosomal recessive neurodegenerative disorder caused by loss-of-function mutations in GBA2 , encoding the non-lysosomal glucocerebrosidase 2. GBA2 deficiency leads to glucosylceramide (GlcCer) accumulation and glucosylated cholesterol (GlcChol) depletion, causing cytoskeletal defects in immature neurons. However, the mechanisms linking lipid dysregulation to neuronal dysfunction remain poorly understood. Methods We modelled GBA2 loss of function by chronic pharmacological inhibition in mouse cerebellar granule neurons (CGNs) and assessed neuronal morphology, synaptic organization, Ca 2+ dynamics, mitochondrial function and actin cytoskeleton during maturation. Proteomic profiling was performed in GBA2-inhibited and GlcChol-supplemented neurons. Findings were validated in a zebrafish gba2 crispant model by evaluating motor behavior, cerebellar development, neuronal organization and mitochondrial function, and in patient-derived fibroblasts carrying a homozygous pathogenic GBA2 variant (NM_020944). The role of RAC1 was studied in both neurons and patients’ cultured skin fibroblasts, and upon rac1 pharmacological inhibition in zebrafish crispants. Results Chronic GBA2 inhibition impaired axonal outgrowth in immature CGNs but not neurite complexity in mature neurons, suggesting morphological compensation. Nevertheless, mature neurons displayed enlarged presynaptic terminals, impaired synaptic vesicle clustering and altered Ca 2+ responses to potassium and glutamate, the latter associated with NMDA receptor redistribution without changes in total receptor levels. Mitochondrial alterations were observed in CGNs, patient fibroblasts and zebrafish, consistent with defective architecture of the mitochondrial network. Proteomics revealed convergent alterations in actin cytoskeleton, synaptic pathways and cellular metabolism following both GBA2 inhibition and GlcChol supplementation. GlcChol bidirectionally regulated RAC1 function, likely altering its spatial distribution rather than its global activation. Confocal imaging confirmed abnormal RAC1 and F-actin localization in patient fibroblasts. Zebrafish gba2 crispants recapitulated motor deficits, Purkinje cell loss, motor neuron disorganization and mitochondrial abnormalities. Pharmacological Rac1 inhibition rescued motor behavior and neuronal organization, linking cytoskeletal disorganization to the observed phenotype in the zebrafish model. Conclusions Our findings identify a pathogenic GlcChol-RAC1-actin signalling axis linking lipid imbalance to synaptic disorganization, NMDA receptor redistribution and mitochondrial dysfunction in SPG46. The selective vulnerability of corticospinal neurons, cerebellar granule neurons and Purkinje cells may reflect their dependence on this pathway. Rac1 inhibition rescues disease phenotypes in vivo , highlighting this pathway as a promising therapeutic target.
proteins
2026-06-04 | LASER couples damage sensing to ESCRT assembly for lysosome repair.
Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of endosomal sorting complex required for transport (ESCRT) I-III rapidly counteracts membrane damage, but it is unclear how ESCRT-I recognizes defective lysosomal membranes. Here, leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we identified LC3/GABARAP-assisted stimulator for ESCRT recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes and couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is TFG, an endoplasmic reticulum exit-site-resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3 and GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit TSG101 via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT-I-II-III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.
2026-02-21 | Structural analysis of the plant glycoside hydrolase family 116 glucosylceramidase AtGCD3 by cryogenic electron microscopy.
Glucosylceramide (GlcCer) is a common glycosphingolipid that accumulates in cells in response to Gaucher disease, diabetes, and skin disorders in humans and is also found in plants. In animals, GlcCer is catabolized by glucosylcerebrosidase 1 and 2 (GBA1 and GBA2). GBA1 is a lysosomal enzyme in glycoside hydrolase (GH) family GH30, while GBA2 is a membrane-associated cytoplasmic protein in family GH116. Currently, there are no experimental structures of eukaryotic GH116 homologues. Although the bacterial TxGH116 β-glucosidase structure was determined by X-ray crystallography, TxGH116 does not hydrolyze glucosylceramides, unlike the animal and plant enzymes. Therefore, we have investigated the structure of plant GH116 (AtGCD3) by cryogenic electron microscopy (Cryo-EM) single-particle analysis. The recombinant AtGCD3 protein was produced in Escherichia coli and purified by immobilized-metal affinity chromatography followed by size-exclusion chromatography. The Cryo-EM structure revealed a unique hexameric arrangement, composed of a dimer of trimers. Hydrophobic interactions and hydrogen bonds stabilize each trimer at the trimer interface. The two trimers stack face-to-face with a slight twist, with salt bridges and hydrogen bonding at their interface. Two α-helices not found in previously described GH116 structures cover the active site, forming two hydrophobic channels that may be involved in glucosylceramide binding. Molecular dynamics simulations showed that glucosylceramide can bind stably in the active site with its lipid tails in these channels. This first eukaryotic structure of a GH116 enzyme generates a template for improved modeling of human GBA2, with implications for treating human diseases, such as Gaucher disease and hereditary spastic paraplegia.
2025-11-27 | Swiss Cheese Gene Is Important for Intestinal Barrier, Microbiome, and Lipid Metabolism Regulation in Drosophila Gut.
Mutations in the human patatin-like lysophospholipase domain containing the 6 gene PNPLA6 encode an evolutionarily conserved (lyso)phospholipase, leading to the development of a complex hereditary spastic paraplegia 39 (SPG 39) and a number of rare severe syndromes in humans. Diseases disrupt the functioning of the nervous and reproductive systems and the gastrointestinal tract. The study aims to investigate the role of the Drosophila melanogaster swiss cheese gene, an ortholog of the human PNPLA6 gene, in gut function. We showed that the swiss cheese gene knockout leads to changes in the morphology of the midgut, disruption of the septate junction structure and the intestinal barrier permeability, and a decrease in the lipid droplet number in enterocytes. As a result of such disturbances, intestinal stem cells (ISCs) proliferation is activated, and the gut microbiome is altered. Ectopic expression of human PNPLA6 leads to the recovery of the intestinal barrier in the fly gut. The example of Drosophila demonstrates the important role of evolutionarily conserved (lyso)phospholipase in intestinal homeostasis.
2025-11-06 | Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.
Hereditary Spastic Paraplegias (HSPs) are a group of heterogeneous neurological diseases characterized by axonal degeneration of corticospinal motor neurons. SPG15, a common autosomal recessive form of HSP, is caused by mutations in the ZFYVE26 gene that encodes the spastizin protein. Spastizin partially localizes to mitochondria, suggesting a potential role in mitochondrial function. To investigate this possibility and explore treatments to mitigate neurodegeneration caused by spastizin deficiency, SPG15 patient-specific induced pluripotent stem cells (iPSCs) were generated from patient fibroblasts and differentiated into cortical projection neurons. The SPG15 iPSC-derived neurons exhibited reduced ATP production compared to control neurons, indicating mitochondrial dysfunction in spastizin-deficient neurons. Also, given increased fragmentation of mitochondria in SPG15 neurons, we examined whether restoring mitochondrial morphology dynamics using P110, a peptide inhibitor of the mitochondrial fission protein DRP1, could protect SPG15 neurons. Indeed, treatment with P110 significantly suppressed the accumulated axonal swellings in SPG15 neurons. Further examination of the underlying mechanisms revealed that P110 restored mitochondrial morphology, ameliorated mitochondrial oxidative stress, and improved mitochondrial health, but it did not affect necrosis-related membrane integrity, suggesting specific targeting of mitochondrial deficits by P110. Furthermore, P110 significantly mitigated disease-related apoptosis in SPG15 neurons. Collectively, these findings reveal that restoring mitochondrial morphology and function using P110 lessens mitochondrial oxidative stress and mitigates degeneration of SPG15 neurons, offering a novel therapeutic approach for SPG15.
2025-10-28 | Botulinum Toxin Treatment in Hereditary Spastic Paraplegia-A Comprehensive Review and Update.
Using Medline and Scopus as search engines, we identified reports of 10 clinical studies (published up to 1 September 2025) on botulinum neurotoxin therapy for hereditary spastic paraplegia (HSP). Nine studies were conducted in adults and one in children. Only one of the ten studies was double-blind and placebo-controlled. The search strategy included only articles published in English and articles providing basic information such as the type of the study, type and dose of the toxin and results of the treatment. Articles not in English, case reports and review articles were excluded. A total of 258 patients were included across all studies. The injected toxin in the open-label studies was botulinumtoxin-A (Botox or Dysport or Xeomin), whereas in the blinded study, the investigators used Prosigne. All open-label studies, which used FDA approved botulinumtoxin-A neurotoxins, demonstrated a degree of motor and non-motor improvement, whereas treatment with Prosigne did not improve patients' function. The possible reasons for this discrepancy between the blinded study and the open-label studies are discussed. We found no studies on the effect of BoNTs on bladder dysfunction in HSP. There is a need for double-blind, placebo-controlled studies assessing the efficacy of FDA-approved botulinum neurotoxins in children and adults affected by hereditary spastic paraparesis. Such studies should also investigate the effect(s) of early botulinum neurotoxin therapy in this disorder. The novelty of this review is that it represents a comprehensive and critical literature review on this subject, with no other studies of this kind published previously. It also includes data not present in previous reviews of this subject.
gene therapies
2026-09-21 | Phenotypic Spectrum and Clinical Approach to Early-Onset Hereditary Spastic Paraplegia.
Early-onset hereditary spastic paraplegias (HSPs) are an underrecognized cause of progressive spasticity, gait impairment, and movement disorders in children and young adults. HSPs frequently mimic cerebral palsy or genetic, metabolic, and acquired disorders, resulting in diagnostic delay. Their broad phenotypic spectrum, encompassing dystonia, parkinsonism, and neurodevelopmental features, makes them highly relevant to movement disorder practitioners across the lifespan. This review summarizes the phenotypic spectrum of early-onset HSP, outlines a practical diagnostic approach for clinicians, and discusses therapeutic strategies. We conducted a narrative review of PubMed-indexed literature through February 2026, supplemented by expert consensus. HSPs typically presenting in childhood and adolescence, inclusive of forms presenting across a broader age spectrum, with attention to subtypes presenting with movement disorders, were considered. Early-onset HSPs encompass both pure and complex forms, with SPG4 (SPAST) and SPG11 (SPG11/KIAA1840) among the most prevalent etiologies. Diagnostic challenges include distinction from cerebral palsy and other movement disorders including dopa-responsive dystonia, and identification of neuroimaging signatures in specific subtypes. A multidisciplinary management approach remains central, with spasticity, movement disorder, and neurological comorbidities each requiring targeted consideration. Disease-modifying therapies are emerging, including gene replacement strategies and antisense oligonucleotide approaches for select subtypes. Early-onset HSPs represent a clinically and genetically heterogeneous group with substantial overlap with movement disorder practice. Awareness of characteristic phenotypes, early genetic testing, and an individualized multidisciplinary approach are essential. Recent advances in natural history characterization and mechanism-targeted therapeutics signal a transition toward disease-modifying treatment strategies and offer cautious optimism for affected individuals.
2026-06-09 | When to Question Cerebral Palsy: Hereditary Spastic Paraplegia Masquerading as Cerebral Palsy (P4-8.006)
To describe a case of progressive lower-extremity weakness initially attributed to CP and subsequently reclassified as HSP following genetic testing.
2026-02-27 | A GJA1 Variant Triggers Earlier SPG4 Onset by Destabilizing Deubiquitinase VCPIP1 to Lower SPASTIN Levels.
SPG4, the most common hereditary spastic paraplegia caused by SPAST variants, exhibits extreme age-at-onset variability, indicative of uncharacterized genetic modifiers. The GJA1R148Q variant (linked to oculodentodigital dysplasia) may modulate SPG4 pathogenesis, yet its underlying molecular mechanism remains undefined. We investigated the molecular mechanism by which GJA1R148Q accelerates early SPG4 onset in a proband with dual SPAST and GJA1 variants, and validated its function as a disease modifier for SPG4. We performed comprehensive clinical phenotyping, segregation analysis, coimmunoprecipitation, ubiquitination analyses, CRISPR-mediated correction in patient induced pluripotent stem cell2013derived organoids, and a targeted deubiquitinase screen. The GJA1R148Q enhanced the physical interaction between SPASTIN and GJA1, accelerated the degradation of deubiquitinase valosin-containing protein interacting protein 1 (VCPIP1), and thereby reduced SPASTIN levels. CRISPR-based reversion of the R148Q restored SPASTIN levels and rescued microtubule-severing function. Notably, maternal relatives carrying the GJA1R148Q allele alone exhibited no neurological abnormalities. The GJA1R148Q variant, although non-neurological in isolation, acts as a disease modifier that precipitates SPG4 by exacerbating SPASTIN haploinsufficiency through destabilization of VCPIP1, positioning GJA1-VCPIP1-SPASTIN signaling as a potential therapeutic axis for SPG4 treatment. © 2026 International Parkinson and Movement Disorder Society.
2026-01-19 | Association of spinal cord structure with cognition in hereditary spastic paraplegia type 5.
Cognitive deficits often accompany brain structural changes, but the association between spinal cord atrophy and cognitive function remains unclear. Spastic paraplegia type 5 (SPG5) is a subtype of hereditary spastic paraplegias (HSPs), caused by mutations in cholesterol metabolism genes, with radiological features of spinal cord atrophy. Our study aims to explore cognitive impairment in SPG5 and its relation to spinal cord structure. We conducted a prospective cross-sectional study with 30 HSPs patients and 47 healthy controls (HC), performing brain and spinal cord MRI and neuropsychological assessments. We investigated correlations between cognitive performance and MRI measurements. Compared to HC, SPG5 patients exhibited significant impairments in the Benton Judgment of Line Orientation Test (p = 0.033), Controlled Oral Word Association Test (p = 0.028), and Symbol Digit Modalities Test (p = 0.023). SPG5 patients also demonstrated significant reductions in spinal cord and thoracic cord cross-sectional area (CSA), anterior-posterior (AP) diameter, and right-left (RL) total (All p < 0.01). Specifically, the thoracic cord RL total was positively correlated with scores on the Brief Visuospatial Memory Test - Revisited delayed recall (BVMT-R DR) and Montreal Cognitive Assessment (MoCA). The spinal cord RL total explained 81% of the variance in BVMT-R DR (p = 0.015) and 74% of the variance in MoCA (p = 0.027). SPG5 patients demonstrate deficits in visuospatial perception, executive function, and information processing speed. Thoracic spinal cord RL total was positively associated with visual memory and global cognition.
2025-11-28 | Intracerebroventricular SPAST-AAV9 gene therapy prevents manifestation of symptoms in a mouse model of SPG4 hereditary spastic paraplegia.
Hereditary spastic paraplegia type 4 is characterized by gait impairments, progressive spasticity, and weakness of the lower limbs, resulting from degeneration of the corticospinal tracts. The disease is caused by mutations of the SPAST gene, which encodes a major isoform of spastin called M87 and a minor isoform called M1. Owing to its N-terminal hydrophobic domain not shared by M87, M1 is the isoform that becomes toxic when mutated. Loss of function of either M1 or M87 or both may also play a role in the disease, sensitizing corticospinal motor neurons to the toxicity of mutant M1. Here, we pursued silence-and-replace gene therapy, which addresses both gain-of-toxicity and loss-of-function components of the disease. We generated an adeno-associated serotype 9 viral vector containing microRNA to stop the expression from the endogenous SPAST gene and cDNA to express healthy human M1 and M87. The vector was introduced by intracerebroventricular injections into newborn pups of SPAST-C448Y, a mouse model of the disease that expresses human mutant spastin and displays adult-onset corticospinal degeneration and gait defects. The treatment successfully replaced both isoforms of endogenous spastin with healthy spastin at physiological levels, and prevented the onset and progression of corticospinal degeneration and gait defects.
oligonucleotides
2025-08-14 | Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.
Motor Neuron Diseases (MNDs) such as Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Hereditary Spastic Paraplegia (HSP), Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1), Multisystem Proteinopathy (MSP), Spinal and Bulbar Muscular Atrophy (SBMA), and ALS associated to Frontotemporal Dementia (ALS-FTD), have traditionally been studied as distinct entities, each one with unique genetic and clinical characteristics. However, emerging research reveals that these seemingly disparate conditions converge on shared molecular mechanisms that drive progressive neuroaxonal degeneration. This narrative review addresses a critical gap in the field by synthesizing the most recent findings into a comprehensive, cross-disease mechanisms framework. By integrating insights into RNA dysregulation, protein misfolding, mitochondrial dysfunction, DNA damage, kinase signaling, axonal transport failure, and immune activation, we highlight how these converging pathways create a common pathogenic landscape across MNDs. Importantly, this perspective not only reframes MNDs as interconnected neurodegenerative models but also identifies shared therapeutic targets and emerging strategies, including antisense oligonucleotides, autophagy modulators, kinase inhibitors, and immunotherapies that transcend individual disease boundaries. The diagnostic and prognostic potential of Neurofilament Light Chain (NfL) biomarkers is also emphasized. By shifting focus from gene-specific to mechanism-based approaches, this paper offers a much-needed roadmap for advancing both research and clinical management in MNDs, paving the way for cross-disease therapeutic innovations.
2023-08-04 | Strumpellin/WASHC5 regulates the structural plasticity of cortical neurons involved in gait coordination.
Strumpellin/Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex subunit 5 (WASHC5) is a core component of the WASH complex, and its mutations confer pathogenicity for hereditary spastic paraplegia (HSP) type SPG8, a rare neurodegenerative gait disorder. WASH complex activates actin-related protein-2/3-mediated actin polymerization and plays a pivotal role in intracellular membrane trafficking in endosomes. In this study, we examined the role of strumpellin in the regulation of structural plasticity of cortical neurons involved in gait coordination. Administration of a lentivirus containing a strumpellin-targeting short hairpin RNA (shRNA) to cortical motor neurons lead to abnormal motor coordination in mice. Strumpellin knockdown using shRNA attenuated dendritic arborization and synapse formation in cultured cortical neurons, and this effect was rescued by wild-type strumpellin expression. Compared with the wild-type, strumpellin mutants N471D or V626F identified in patients with SPG8 exhibited no differences in rescuing the defects. Moreover, the number of F-actin clusters in neuronal dendrites was decreased by strumpellin knockdown and rescued by strumpellin expression. In conclusion, our results indicate that strumpellin regulates the structural plasticity of cortical neurons via actin polymerization.
2022-05-03 | Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4.
While the anticipated rise of disease-modifying therapies calls for reliable trial outcome parameters, fluid biomarkers are lacking in spastic paraplegia type 4 (SPG4), the most prevalent form of hereditary spastic paraplegia. We therefore investigated serum neurofilament light chain (sNfL) as a potential therapy response, diagnostic, monitoring, and prognostic biomarker in SPG4. We assessed sNfL levels in 93 patients with SPG4 and 60 healthy controls. The longitudinal study of sNfL levels in SPG4 patients covered a baseline, 1-year follow-up and 2-year follow-up visit. Levels of sNfL were significantly increased in patients with genetically confirmed SPG4 compared to healthy controls matched in age and sex (p = 0.013, r = 0.2). Our cross-sectional analysis revealed a greater difference in sNfL levels between patients and controls in younger ages with decreasing fold change of patient sNfL elevation at older ages. Over our observational period of 2 years, sNfL levels remained stable in SPG4 patients. Disease severity and progression did not correlate with sNfL levels. Our longitudinal data indicate a stable turnover of sNfL in manifest SPG4; therefore, sNfL levels are not suitable to monitor disease progression in SPG4. However, sNfL may be valuable as a therapy response biomarker, since its turnover could be modified by interventions. As the course of sNfL levels appears to be most dynamic around the onset of SPG4, the ability to detect a therapy response appears to be especially promising in younger patients, matching the need to initiate treatment in early disease stages.
2020-09-04 | Suppression of spastin Mutant Phenotypes by Pak3 Loss Implicates a Role for Reactive Glia in AD-HSP
Neurodegenerative mechanisms due to mutations in spastin currently center on neuronal defects, primarily in microtubule and endomembrane regulation. Spastin loss in Drosophila larvae compromises neuronal microtubule distribution, alters synaptic bouton morphology, and weakens synaptic transmission at glutamatergic neuromuscular junction (NMJ) synapses. Pak3, a p21-activated kinase that promotes actin polymerization and filopodial projections, is required for these spastin mutant defects; animals lacking both genes have normal NMJs. Here we show that Pak3 is expressed in central and peripheral glial populations, and reduction of Pak3 specifically in subperineurial glial cells is sufficient to suppress the phenotypes associated with spastin loss. Subperineurial glia in the periphery ensheathe motor neuron axons and have been shown to extend actin-based projections that regulate synaptic terminals during normal NMJ development. We find that these subperineurial glial projections are Pak3-dependent and nearly twice as frequent in spastin mutants, while in Pak3, spastin double mutants, neither glial projections nor synaptic defects are observed. Spastin deficiency thus increases Pak3-dependent subperineurial glia activity, which is in turn required for neuronal defects. Our results demonstrate a central role for Pak3-mediated, altered glial behavior in the neuronal defects due to spastin loss, and suggest that a similar reactive glia-mediated mechanism may underlie human AD-HSP pathogenesis.
2019-12-06 | MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons.
Recent reports, including ours, have indicated that microRNA (miR)-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a potential therapeutic target for the treatment of atherosclerosis. Here, we show that SPAST, which encodes a microtubule-severing protein called SPASTIN, was a novel target gene of miR-33 in human. Actually, the miR-33 binding site in the SPAST 3'-UTR is conserved not in mice but in mid to large mammals, and it is impossible to clarify the role of miR-33 on SPAST in mice. We demonstrated that inhibition of miR-33a, a major form of miR-33 in human neurons, via locked nucleic acid (LNA)-anti-miR ameliorated the pathological phenotype in hereditary spastic paraplegia (HSP)-SPG4 patient induced pluripotent stem cell (iPSC)-derived cortical neurons. Thus, miR-33a can be a potential therapeutic target for the treatment of HSP-SPG4.
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2026-09-03 | Validation of a Cellular Imaging-Based Method as a Potential Biomarker for SPG4 Hereditary Spastic Paraplegia.
Hereditary Spastic Paraplegia (HSP) comprises a group of rare genetic diseases characterized by length-dependent axonal degeneration of the corticospinal tracts and dorsal columns, whose main clinical feature is spastic gait. Pathogenic variants in the SPG4 gene cause Spastic Paraplegia Type 4 (SPG4-HSP), the most common form of HSP. SPG4/SPAST encodes spastin, a protein involved in microtubule regulation and lipid droplet behavior. SPG4-HSP shows extreme heterogeneity in both clinical manifestations and genetics. Although no cure is currently available, several strategies aimed at restoring spastin levels are emerging; however, SPG4-HSP still lacks accessible cellular readouts for clinical studies. This study evaluates a cell-imaging approach that quantifies the distance between nucleus and cell centroid (dcnc) in peripheral blood mononuclear cells (PBMCs) in a genetically and clinically heterogeneous SPG4-HSP cohort. PBMCs from 48 molecularly confirmed SPG4-HSP patients and 21 healthy controls (HC) were analyzed by automated cell imaging. Dcnc and additional cytoskeletal and lipid droplet-related parameters were measured. Patient-level discrimination was assessed via cross-validated classification; correlations with molecular and clinical features were explored. At the patient level, dcnc distinguishes SPG4-HSP from HC, independently of mutation type and disease severity, supporting robust cross-validated classification and inverse correlation with spastin protein levels. Dcnc is a robust, non-invasive, and mutation-independent cellular candidate biomarker for SPG4-HSP. It also offers preliminary evidence consistent with spastin target engagement supporting evaluation in future clinical trials.
2025-10-03 | Development of a Human iPSC-Derived "Corticospinal Tract-on-a-Chip" for Neurodegenerative Disease Research.
Degeneration of the corticospinal tract is a central feature in a number of neurodegenerative disorders and leads to significant disability. However, modeling corticospinal neuron (CSN) pathology and corticospinal connectivity in neurological disorders is particularly challenging. While rodent models are important for understanding early degeneration of CSN, interspecies differences in corticospinal connectivity and challenges of in vivo study suggest that human in vitro models of corticospinal biology may be ripe for development. Human induced pluripotent stem cells (hiPSC) are promising tools for overcoming intrinsic limitations that arise from physiological differences between rodents and humans. We have developed an innovative hiPSC-based microfluidic platform for modeling human CSN and spinal motor neuron (SpMN) connectivity. The incorporation of regionally specific astrocyte subtypes (cortical and spinal) in addition to CSNs and SpMNs in this newly designed system allows for the modeling of both regional and neural cell-subtype interactions. Using this model, multielectrode array electrophysiology reveals the maturation of both cortical and spinal motor neurons over the time course of 12 weeks. Retrograde labeling methods demonstrate synaptic connectivity between corticospinal and spinal motor neurons. Optogenetic strategies to selectively activate excitatory CNs attenuated by glutamate receptor antagonism confirms the functional relevance of the model. Incorporating morphological, electrophysiological and physiological measures of corticospinal connectivity, this platform is a versatile model for use in neurodegenerative disease research and for the future development of targeted CSN therapies. Degeneration of the corticospinal tract is a key feature of numerous neurodegenerative diseases, yet current in vitro models lack the anatomical and functional fidelity to study this system. We developed a human iPSC-derived "Corticospinal Tract-on-a-Chip" using a multielectrode array platform that incorporates regionally patterned cortical and spinal neurons and astrocytes. This model demonstrates structural and functional synaptic connectivity and enables longitudinal electrophysiological recordings. Critically, it supports compartment-specific manipulation and real-time analysis of CST network dynamics, capabilities lacking in existing systems. By mimicking human corticospinal physiology in vitro , this platform offers a novel tool for mechanistic investigation and preclinical testing of CST-targeted therapies. It holds broad relevance for studying disorders such as ALS, hereditary spastic paraplegia, and primary lateral sclerosis.
2025-03-18 | Toxoplasmosis accelerates the progression of hereditary spastic paraplegia.
The parasitic protozoa Toxoplasma gondii chronically infects the central nervous system of an estimated one-third of the human population. Infection is generally subclinical, but immunocompromised individuals can experience a variety of neurological symptoms. Meta-analyses of T. gondii seropositivity have suggested a correlation between T. gondii infection and neurologic disease. Although mechanistic studies on the relationship between T. gondii infection and neurologic disease have been attempted in mice, they are particularly susceptible to T. gondii, making them an effective model for investigating mechanisms of infection, but not ideal for examining the relationship between long-term chronic T. gondii infection and neurologic disease. Rats more closely mimic human T. gondii cyst levels after acute infection, but a lack of rat models for neurologic disease has limited studies on the interplay between T. gondii infection and neurologic disease progression. We have employed a previously characterized rat model of a complex form of hereditary spastic paraplegia (HSP), a class of neurodegenerative disorders that cause axonal degeneration and lower limb spasticity, in order to assess the effect of chronic T. gondii infection on neurodegenerative disease. We find that infected rats with hereditary spastic paraplegia exhibit significantly exacerbated behavioral and neuromorphological HSP symptoms compared with uninfected HSP mutant rats, with little correlative effect in infected versus uninfected control animals. We further find that all infected rats, regardless of genotype, exhibit a robust immune response to T. gondii infection, presenting with parasite levels below the limit of detection of multiple assays of parasitemia and exhibiting no detectable increase in neuroinflammation 7 weeks post-infection. These results suggest that chronic undetected T. gondii infection may exacerbate neurodegenerative disease even in immunocompetent individuals and may contribute to neurodegenerative disease heterogeneity.IMPORTANCEThe long-term consequences of previous acute infections are poorly understood but are becoming increasingly appreciated, particularly in the era of long COVID. Altered progression of other diseases later in life may be among the long-term consequences of previous infections. Here, we investigate the relationship between previous infections with the parasite Toxoplasma gondii, which infects ~30% of the global population, and neurodegenerative disease using a rat model of hereditary spastic paraplegia (HSP). We find that previous infections with T. gondii accelerate motor dysfunction in HSP rats, despite robust clearance of the parasite by infected rats. Our results suggest that previously cleared infections may alter the progression of other diseases later in life and contribute to neurodegenerative disease heterogeneity.
2024-03-14 | Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.
Hereditary spastic paraplegias (HSPs) comprise a family of degenerative diseases mostly hitting descending axons of corticospinal neurons. Depending on the gene and mutation involved, the disease could present as a pure form with limb spasticity, or a complex form associated with cerebellar and/or cortical signs such as ataxia, dysarthria, epilepsy, and intellectual disability. The progressive nature of HSPs invariably leads patients to require walking canes or wheelchairs over time. Despite several attempts to ameliorate the life quality of patients that have been tested, current therapeutical approaches are just symptomatic, as no cure is available. Progress in research in the last two decades has identified a vast number of genes involved in HSP etiology, using cellular and animal models generated on purpose. Although unanimously considered invaluable tools for basic research, those systems are rarely predictive for the establishment of a therapeutic approach. The advent of induced pluripotent stem (iPS) cells allowed instead the direct study of morphological and molecular properties of the patient's affected neurons generated upon in vitro differentiation. In this review, we revisited all the present literature recently published regarding the use of iPS cells to differentiate HSP patient-specific neurons. Most studies have defined patient-derived neurons as a reliable model to faithfully mimic HSP in vitro, discovering original findings through immunological and -omics approaches, and providing a platform to screen novel or repurposed drugs. Thereby, one of the biggest hopes of current HSP research regards the use of patient-derived iPS cells to expand basic knowledge on the disease, while simultaneously establishing new therapeutic treatments for both generalized and personalized approaches in daily medical practice.
2021-11-25 | Generation of induced pluripotent stem cell line (ZZUi030-A) from a patient with spastic paraplegia type 7.
Spastic paraplegia type 7 is a rare and classical monogenic inherited neurodegenerative disease caused by heterozygous mutations in the SPG7 gene. The principle clinical features include progressive spasms of the lower limbs, scissor gait, and muscle weakness. The disease currently has no effective treatment. In this study, we obtained dermal fibroblasts from a patient, which were successfully transformed into induced pluripotent stem cells (iPSCs) by employing reprogramming plasmids expressing OCT3/4, SOX2, KLF4, LIN28, and L-MYC. Our method provides a resource for mechanism exploration, drug research, cell transplantation, and gene therapy.
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Drug Discovery Landscape
3 orphan drug designations for Hereditary spastic paraplegia.
3 orphan drug designations for Hereditary spastic paraplegia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Self-complimentary adeno-associated virus 9 gene therapy containing codon optimized human AP4M1 (melpida) | gene therapies | FDA | Elpida Therapeutics | |
adeno-associated virus serotype 9 gene transfer vector expressing human AP4B1 cDNA | gene therapies | FDA | BlackfinBio Limited | |
L-threonine | small molecules | FDA | — | Interneuron Pharmaceuticals, Inc. |
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