RARE DISEASE
Autosomal dominant spastic paraplegia type 4
Autosomal dominant spastic paraplegia type 4
Autosomal dominant spastic paraplegia type 4
Synonyms: SPG4
Synonyms: SPG4
Synonyms: SPG4
Drug discovery
0
drugs
With orphan designations
Overview
Autosomal dominant spastic paraplegia type 4 (SPG4) is the most common hereditary spastic paraplegia, caused by SPAST gene mutations leading to spastin deficiency. It primarily presents with progressive lower-limb spasticity, weakness, and urinary urgency, typically starting in adulthood (3rd–5th decade). While 70–80% exhibit a pure phenotype, complex cases may include cognitive decline, neuropathy, or cerebellar ataxia. High intrafamilial variability and age-dependent penetrance (up to 90%) are hallmarks [1][2][6][13].
Therapies
Symptomatic management: Oral antispasmodics (baclofen, tizanidine), intrathecal baclofen pumps, and botulinum toxin [11][14][17].
Rehabilitation: Targeted physiotherapy to improve gait and reduce spasticity [14][17].
Experimental approaches: CRL4 inhibition (NSC1892) and microtubule stabilizers (noscapine) in preclinical studies [3][7].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
75 drug discovery papers about Autosomal dominant spastic paraplegia type 4, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
75 drug discovery papers about Autosomal dominant spastic paraplegia type 4, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-29 | Alu-mediated SPAST deletion impairs golgi zinc transport and reveals a druggable vulnerability.
Alu elements are primate-specific retrotransposons known to mediate structural genomic alterations associated with neurological disorders, yet their underlying disease mechanism remains incompletely understood. Here, we leveraged human pluripotent stem cell-derived cortical organoids and xenografts to model an Alu-mediated exon 17 deletion in the SPAST gene, a frequent cause of hereditary spastic paraplegia (SPG4) with dementia. This deletion generates fusion transcripts between SPAST and the downstream gene SLC30A6, resulting in reduced expression of ZnT6, the Golgi-resident zinc transporter encoded by SLC30A6. In SPASTΔe17 organoids, we detected pronounced cytosolic zinc accumulation, Golgi fragmentation, lipid dysregulation, and increased aggregation of Aβ and ubiquitin. These phenotypes were further exacerbated in xenograft models, concomitant with ubiquitin-positive inclusions resembling those found in patients' brains. Knockdown of SLC30A6 in control organoids recapitulated the neurodegenerative features, supporting a critical role of ZnT6 in maintaining neuronal homeostasis. Intervention with TPEN, a zinc-specific chelator, or a GRASP55-blocking antibody to prevent Golgi fragmentation significantly restored Golgi integrity and reduced Aβ levels. Notably, immunohistochemistry revealed heterogeneous ZnT6 expression in AD brains; however, both ZnT6-low and ZnT6-high cases consistently exhibited elevated p-GM130, a marker of Golgi fragmentation. Finally, we detected a SPAST-SLC30A6 chimeric transcript in brain tissue from a sporadic AD patient. Together, our findings identify a primate-specific cascade linking Alu-mediated genomic rearrangements to zinc dyshomeostasis and Golgi pathology and suggest that dysregulation of the ZnT6-Golgi axis may represent a vulnerability and therapeutic target in structural variant-driven neurodegeneration and possibly in a subset of sporadic cases.
2026-02-25 | Modeling spastic paraplegia 4 with corticospinal motor neuron-enriched cortical organoids reveals genotype-phenotype and HDAC6-targetable pathology.
Spastic paraplegia 4 (SPG4), the most common form of hereditary spastic paraplegia, causes progressive gait deficiency due to corticospinal tract degeneration. SPG4 results from mutations in the SPAST gene, which encodes spastin, a microtubule-severing AAA-ATPase. To dissect genotype-phenotype relationships, we generated isogenic human induced pluripotent stem cell lines carrying either an SPAST missense (SPASTWT/C448Y) or truncation (SPASTWT/S245X) mutation and differentiated them into corticospinal motor neuron-enriched cortical organoids. These models revealed mutation-specific patterns of aberrant neuronal activity, microtubule hypoacetylation, and axonal degeneration. We identified mutant M1-spastin-induced hyperactivation of histone deacetylase 6 (HDAC6), a major tubulin deacetylase, as the key pathogenic culprit. Pharmacological inhibition of HDAC6 with tubastatin A restored microtubule acetylation and rescued axonal degeneration in organoids, with corresponding improvements in corticospinal tract integrity and gait defects in SPG4 transgenic mice. Our study uncovers HDAC6 hyperactivation as a targetable mechanism for SPG4 and verifies human organoids as a platform for therapeutic discovery.
2026-01-16 | Serendipitous Symptom Control: Allopurinol for Spasticity in a Case of SPG4-Linked Hereditary Spastic Paraplegia-A Case Report.
In a patient with genetically confirmed SPG4-linked hereditary spastic paraplegia, initiation of allopurinol for asymptomatic hyperuricemia led to rapid and sustained improvement in lower limb spasticity, allowing marked reduction of antispasmodic therapy. This serendipitous finding suggests a potential therapeutic role of xanthine oxidase inhibition in managing HSP-related spasticity.
2025-12-17 | Reversing Autophagy Inhibition Ameliorates Neurodegeneration in Hereditary Spastic Paraplegia Caused by a Degradation-Resistant SPAST Mutation.
Hereditary spastic paraplegias (HSPs) are monogenic neurodegenerative disorders, and SPAST mutations causing spastic paraplegia type 4 (SPG4) represent the most common form of HSP. SPAST mutations elevate SPASTIN protein levels beyond haploinsufficiency, but the mechanisms and downstream consequences are unclear. We identified a de novo SPAST missense variant (p.I344E) in a young Chinese female with SPG4. Wild-type (WT) and mutant (I344E/K) SPAST constructs were expressed in HEK293 for biochemical and functional assays including cycloheximide chase, ubiquitination analysis, and immunofluorescence. Leveraging somatic cell reprogramming and CRISPR-based gene editing, we generated patient-derived induced pluripotent stem cells (iPSCs) and their isogenic controls. Both lines were differentiated into cerebral organoids. I344E/K-SPASTIN exhibited markedly higher steady-state levels than WT-SPASTIN owing to impaired ubiquitin-proteasome-mediated degradation; the I344E variant showed the greatest accumulation. Mutant SPASTIN mislocalized in cells, displayed diminished microtubule-severing activity, and elevated acetylated tubulin-phenotypes that were rescued by overexpression of WT-SPASTIN. In patient cerebral organoids, the I344E mutation led to increased p62/SQSTM1 aggregates, reduced autophagic flux, and enhanced neuronal death. Rapamycin restored autophagy, decreased p62 levels, and reduced cell death. Our study provides evidence linking autophagy dysfunction to SPG4 pathogenesis and demonstrates that the I344E mutation acts through a gain-of-function mechanism. These findings challenge the prevailing haploinsufficiency model and implicate autophagy modulation as a potential therapeutic strategy for SPG4 and possibly other HSPs. © 2025 International Parkinson and Movement Disorder Society.
2025-08-12 | Genotype-Phenotype Distinctions in Spastic Paraplegia 4 Reveal HDAC6 as a Therapeutic Target.
Spastic Paraplegia 4 (SPG4) is the most prevalent form of Hereditary Spastic Paraplegia (HSP), a neurodegenerative disorder characterized by progressive lower limb spasticity and debilitating gait impairment, primarily driven by axonal degeneration of corticospinal motor neurons (CSMNs). Caused by mutations in the SPAST gene encoding spastin, an AAA-ATPase involved in microtubule severing and intracellular organelle function, SPG4 accounts for 40-50% of autosomal dominant HSP cases, yet without effective treatments. Although reduced microtubule acetylation has emerged as a key pathological mechanism, whether and how distinct mutations lead to microtubule deacetylation and subsequent neurodegeneration remains unclear. To address this, we generated isogenic human induced pluripotent stem cell (hiPSC) lines with two distinct heterozygous SPAST mutations - SPAST WT/C448Y (missense) and SPAST WT/S245X (truncation). Employing an innovative differentiation protocol, we created human motor cortical organoids enriched in CSMNs, providing a robust platform to study SPG4 pathophysiology. These organoids revealed striking genotype-phenotype distinctions, with mutation-specific variations in CSMN loss, axonal degeneration and neuronal activities, mirroring clinical heterogeneity. Mechanistic studies identified aberrant activation of histone deacetylase 6 (HDAC6), a major neuronal microtubule deacetylase, as a key driver of SPG4 pathology. This dysregulation was specifically attributed to mutant M1-spastin, the longer isoform of spastin. Remarkably, pharmacological inhibition of HDAC6 with Tubastatin A restored microtubule acetylation status and mitigated axonal degeneration in both SPAST-mutant organoids, with corresponding improvements in corticospinal tract integrity and gait deficits validated in SPG4-transgenic mice. Collectively, our study establishes isogenic hiPSC-derived motor cortical organoids as a robust human model for corticospinal motor neuron degeneration and identifies HDAC6 hyperactivation as a central pathogenic mechanism and viable therapeutic target in SPG4.
proteins
2024-11-30 | Unraveling Isoform Complexity: The Roles of M1- and M87-Spastin in Spastic Paraplegia 4 (SPG4).
Spastic Paraplegia 4 (SPG4) is a debilitating neurodegenerative disorder characterized by progressive muscle weakness and spasticity in the lower limbs, often leading to gait impairment. Central to SPG4 pathology is the die-back degeneration of corticospinal tracts, primarily driven by mutations in the spastin protein encoded by the SPAST gene. SPAST gives rise to two major spastin isoforms, M1- and M87-spastin, which are generated from distinct translation initiation sites. Although spastin is implicated in various cellular functions, the specific roles of each isoform in the pathogenesis of SPG4 remain poorly understood. This review offers an overview of the genetic and structural organization of the M1- and M87-spastin isoforms, highlighting their distinct and overlapping functions, and exploring their potential roles in the haploinsufficiency and gain-of-toxicity mechanisms underlying SPG4. We also present a novel perspective on the evolutionary emergence of M1-spastin and its potential unique involvement in the pathogenesis of SPG4. Drawing upon the latest research, we propose an intriguing hypothesis regarding the hetero-oligomerization of M1- and M87-spastin, exploring how their interaction may drive disease progression and open new avenues for therapeutic intervention. By integrating the current research with these fresh insights, we seek to illuminate the complex molecular mechanisms driving SPG4 and foster the development of innovative therapeutic strategies. This review not only incorporates existing knowledge but also lays the groundwork for future studies aimed at uncovering the isoform-specific roles of spastin in SPG4, with the ultimate goal of advancing targeted treatments for this challenging neurodegenerative disorder. © 2024 International Parkinson and Movement Disorder Society.
2014-12-03 | Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients' neurons.
The hereditary spastic paraplegias (HSPs) are a heterogeneous group of motorneuron diseases characterized by progressive spasticity and paresis of the lower limbs. Mutations in Spastic Gait 4 (SPG4), encoding spastin, are the most frequent cause of HSP. To understand how mutations in SPG4 affect human neurons, we generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of two patients carrying a c.1684C>T nonsense mutation and from two controls. These SPG4 and control hiPSCs were able to differentiate into neurons and glia at comparable efficiency. All known spastin isoforms were reduced in SPG4 neuronal cells. The complexity of SPG4 neurites was decreased, which was paralleled by an imbalance of axonal transport with less retrograde movement. Prominent neurite swellings with disrupted microtubules were present in SPG4 neurons at an ultrastructural level. While some of these swellings contain acetylated and detyrosinated tubulin, these tubulin modifications were unchanged in total cell lysates of SPG4 neurons. Upregulation of another microtubule-severing protein, p60 katanin, may partially compensate for microtubuli dynamics in SPG4 neurons. Overexpression of the M1 or M87 spastin isoforms restored neurite length, branching, numbers of primary neurites and reduced swellings in SPG4 neuronal cells. We conclude that neurite complexity and maintenance in HSP patient-derived neurons are critically sensitive to spastin gene dosage. Our data show that elevation of single spastin isoform levels is sufficient to restore neurite complexity and reduce neurite swellings in patient cells. Furthermore, our human model offers an ideal platform for pharmacological screenings with the goal to restore physiological spastin levels in SPG4 patients.
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.
2026-03-09 | Spastin Is Required to Prevent SPAST-Related Demyelination.
Mutations in the SPAST gene, encoding the microtubule-severing protein Spastin, cause the most common type of hereditary spastic paraplegia (HSP): SPG4, a disorder primarily characterized by length-dependent axonal degeneration. Clinically, most SPG4 patients present with a pure phenotype marked by progressive spasticity in the lower extremities. It has also been reported that complex cases exhibit demyelination and cognitive deficits. Additionally, some SPAST variants have been determined in patients with multiple sclerosis (MS), indicating potential shared pathological mechanisms. Spastin is known to promote axonal regeneration by remodeling microtubules, whereas mutant Spastin disrupts microtubule dynamics and causes axonal transport defects in SPG4. However, whether Spastin dysfunction impairs regenerative processes such as myelination remains unknown. In this study, we investigated whether the SPG4-associated SPAST mutations affect axonal myelination. Using an in vitro cortical neuron-oligodendrocyte co-culture model, we found that pathogenic SPAST mutations result in a significant reduction in the myelination index. Furthermore, a cuprizone-induced demyelination mouse model revealed a decrease in Spastin protein levels in demyelinated white matter. Given Spastin's role in axonal regeneration, we hypothesized that Spastin may also protect against demyelination. Supporting this, wild-type Spastin expression protected neurons from demyelination in a cuprizone-induced cell culture demyelination model. Together, these results suggest a role for Spastin in axonal myelination, and its dysfunction may compromise myelin stability. Our findings highlight that impaired myelin stability may represent a secondary pathological feature of SPG4, contributing to disease complexity. This dual role of Spastin in axonal maintenance and myelin stability suggests its potential relevance for contributing to complex forms of SPG4.
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.
2026-02-25 | MDSGene Systematic Review of Common Forms of Dominant Hereditary Spastic Paraplegia: Novel Insights.
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by progressive spasticity and lower limb weakness. The most common forms of autosomal dominant HSP are caused by pathogenic variants in SPAST (SPG4 or HSP-SPAST), ATL1 (SPG3A or HSP-ATL1), and REEP1 (SPG31 or HSP-REEP1). We performed an MDSGene Systematic Review to determine in-depth genotype-phenotype associations and to estimate longitudinal progression, to inform prognostication and clinical trial stratification. We systematically collected demographic, phenotypic, and genetic data from published reports of individuals affected by these forms of HSP using the MDSGene protocol. We reviewed 2177 affected individuals, including 1670 individuals with HSP-SPAST, 356 with HSP-ATL1 and 151 with HSP-REEP1. HSP-ATL1 was associated with an earlier age at onset compared to HSP-SPAST and HSP-REEP1. Toe-walking was more frequently reported in HSP-ATL1 (10.4%) and HSP-REEP1 (3.3%) than HSP-SPAST (0.3%). Upper limb hyperreflexia and abnormalities of bladder function were more frequent in HSP-SPAST than HSP-ATL1 or HSP-REEP1. Sufficient data was available to estimate disease progression for HSP-SPAST; this showed that Spastic Paraplegia Rating Scale (SPRS) scores increased with increasing age at examination after the age of 40 years. Truncating variants were more frequent in HSP-SPAST and HSP-REEP1 than HSP-ATL1. Overall, HSP-ATL1, HSP-SPAST and HSP-REEP1 demonstrated differences in clinical phenotypes. To our knowledge, this is the first systematic review to model longitudinal progression using SPRS scores in HSP. Missing data is a limiting factor in all these comparisons, highlighting the need for uniform data collection. Online resources can be found at https://www.mdsgene.org/.
2026-02-16 | Two pathogenetic intronic variants in SPG4/SPAST and expansion of the clinical presentation.
Hereditary Spastic Paraplegia (HSP) is a group of inherited neurodegenerative disorders primarily characterized by progressive lower limb spasticity and weakness. Among the various genetic causes of HSP, pathogenetic variants in SPG4/SPAST are the most frequently identified, making them the leading molecular cause of autosomal dominant HSP. The SPAST gene encodes spastin, a protein involved in microtubule dynamics. In this study, we focused on the functional characterization of two specific intronic variants in SPAST absent or present at a very low frequency in GnomAD database and with conflicting classification of pathogenicity, c.1245 + 5G > A and c.1493 + 2_1493 + 5del respectively. These variants were identified in two independent families, one of Brazilian origin and the other of Japanese descent. Our data shows that the splicing variants impact splicing. Furthermore, through segregation analysis and clinical assessments, we provided a detailed description of the affected individuals, emphasizing the clinical presentation associated with these genetic changes. Notably, in both families, the identified variants co-segregated symptoms consistent with anorexia nervosa, suggesting a potential, previously unrecognized association between SPAST pathogenic variants and disordered eating behaviors. Our findings contributed to the expanding clinical spectrum of SPG4-associated HSP and highlighted the importance of characterizing intronic SPAST variants. The characterization of intronic pathogenetic variants enhanced our understanding of their potential pathogenic mechanisms, which may have implications for both genetic diagnosis and the broader clinical management of HSP.
cell therapies
2022-10-24 | Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia
Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders, characterized by progressive lower limb spasticity and weakness resulting from retrograde axonal degeneration of motor neurons (MNs). Here, we generated in vitro human neuromuscular junctions (NMJs) from five HSP patient-specific induced pluripotent stem cell (hiPSC) lines, by means of microfluidic strategy, to model disease-relevant neuropathologic processes. The strength of our NMJ model lies in the generation of lower MNs and myotubes from autologous hiPSC origin, maintaining the genetic background of the HSP patient donors in both cell types and in the cellular organization due to the microfluidic devices. Three patients characterized by a mutation in the SPG3a gene, encoding the ATLASTIN GTPase 1 protein, and two patients with a mutation in the SPG4 gene, encoding the SPASTIN protein, were included in this study. Differentiation of the HSP-derived lines gave rise to lower MNs that could recapitulate pathological hallmarks, such as axonal swellings with accumulation of Acetyl-α-TUBULIN and reduction of SPASTIN levels. Furthermore, NMJs from HSP-derived lines were lower in number and in contact point complexity, denoting an impaired NMJ profile, also confirmed by some alterations in genes encoding for proteins associated with microtubules and responsible for axonal transport. Considering the complexity of HSP, these patient-derived neuronal and skeletal muscle cell co-cultures offer unique tools to study the pathologic mechanisms and explore novel treatment options for rescuing axonal defects and diverse cellular processes, including membrane trafficking, intracellular motility and protein degradation in HSP.
small molecules
2026-07-29 | Alu-mediated SPAST deletion impairs golgi zinc transport and reveals a druggable vulnerability.
Alu elements are primate-specific retrotransposons known to mediate structural genomic alterations associated with neurological disorders, yet their underlying disease mechanism remains incompletely understood. Here, we leveraged human pluripotent stem cell-derived cortical organoids and xenografts to model an Alu-mediated exon 17 deletion in the SPAST gene, a frequent cause of hereditary spastic paraplegia (SPG4) with dementia. This deletion generates fusion transcripts between SPAST and the downstream gene SLC30A6, resulting in reduced expression of ZnT6, the Golgi-resident zinc transporter encoded by SLC30A6. In SPASTΔe17 organoids, we detected pronounced cytosolic zinc accumulation, Golgi fragmentation, lipid dysregulation, and increased aggregation of Aβ and ubiquitin. These phenotypes were further exacerbated in xenograft models, concomitant with ubiquitin-positive inclusions resembling those found in patients' brains. Knockdown of SLC30A6 in control organoids recapitulated the neurodegenerative features, supporting a critical role of ZnT6 in maintaining neuronal homeostasis. Intervention with TPEN, a zinc-specific chelator, or a GRASP55-blocking antibody to prevent Golgi fragmentation significantly restored Golgi integrity and reduced Aβ levels. Notably, immunohistochemistry revealed heterogeneous ZnT6 expression in AD brains; however, both ZnT6-low and ZnT6-high cases consistently exhibited elevated p-GM130, a marker of Golgi fragmentation. Finally, we detected a SPAST-SLC30A6 chimeric transcript in brain tissue from a sporadic AD patient. Together, our findings identify a primate-specific cascade linking Alu-mediated genomic rearrangements to zinc dyshomeostasis and Golgi pathology and suggest that dysregulation of the ZnT6-Golgi axis may represent a vulnerability and therapeutic target in structural variant-driven neurodegeneration and possibly in a subset of sporadic cases.
2026-02-25 | Modeling spastic paraplegia 4 with corticospinal motor neuron-enriched cortical organoids reveals genotype-phenotype and HDAC6-targetable pathology.
Spastic paraplegia 4 (SPG4), the most common form of hereditary spastic paraplegia, causes progressive gait deficiency due to corticospinal tract degeneration. SPG4 results from mutations in the SPAST gene, which encodes spastin, a microtubule-severing AAA-ATPase. To dissect genotype-phenotype relationships, we generated isogenic human induced pluripotent stem cell lines carrying either an SPAST missense (SPASTWT/C448Y) or truncation (SPASTWT/S245X) mutation and differentiated them into corticospinal motor neuron-enriched cortical organoids. These models revealed mutation-specific patterns of aberrant neuronal activity, microtubule hypoacetylation, and axonal degeneration. We identified mutant M1-spastin-induced hyperactivation of histone deacetylase 6 (HDAC6), a major tubulin deacetylase, as the key pathogenic culprit. Pharmacological inhibition of HDAC6 with tubastatin A restored microtubule acetylation and rescued axonal degeneration in organoids, with corresponding improvements in corticospinal tract integrity and gait defects in SPG4 transgenic mice. Our study uncovers HDAC6 hyperactivation as a targetable mechanism for SPG4 and verifies human organoids as a platform for therapeutic discovery.
2026-01-16 | Serendipitous Symptom Control: Allopurinol for Spasticity in a Case of SPG4-Linked Hereditary Spastic Paraplegia-A Case Report.
In a patient with genetically confirmed SPG4-linked hereditary spastic paraplegia, initiation of allopurinol for asymptomatic hyperuricemia led to rapid and sustained improvement in lower limb spasticity, allowing marked reduction of antispasmodic therapy. This serendipitous finding suggests a potential therapeutic role of xanthine oxidase inhibition in managing HSP-related spasticity.
2025-12-17 | Reversing Autophagy Inhibition Ameliorates Neurodegeneration in Hereditary Spastic Paraplegia Caused by a Degradation-Resistant SPAST Mutation.
Hereditary spastic paraplegias (HSPs) are monogenic neurodegenerative disorders, and SPAST mutations causing spastic paraplegia type 4 (SPG4) represent the most common form of HSP. SPAST mutations elevate SPASTIN protein levels beyond haploinsufficiency, but the mechanisms and downstream consequences are unclear. We identified a de novo SPAST missense variant (p.I344E) in a young Chinese female with SPG4. Wild-type (WT) and mutant (I344E/K) SPAST constructs were expressed in HEK293 for biochemical and functional assays including cycloheximide chase, ubiquitination analysis, and immunofluorescence. Leveraging somatic cell reprogramming and CRISPR-based gene editing, we generated patient-derived induced pluripotent stem cells (iPSCs) and their isogenic controls. Both lines were differentiated into cerebral organoids. I344E/K-SPASTIN exhibited markedly higher steady-state levels than WT-SPASTIN owing to impaired ubiquitin-proteasome-mediated degradation; the I344E variant showed the greatest accumulation. Mutant SPASTIN mislocalized in cells, displayed diminished microtubule-severing activity, and elevated acetylated tubulin-phenotypes that were rescued by overexpression of WT-SPASTIN. In patient cerebral organoids, the I344E mutation led to increased p62/SQSTM1 aggregates, reduced autophagic flux, and enhanced neuronal death. Rapamycin restored autophagy, decreased p62 levels, and reduced cell death. Our study provides evidence linking autophagy dysfunction to SPG4 pathogenesis and demonstrates that the I344E mutation acts through a gain-of-function mechanism. These findings challenge the prevailing haploinsufficiency model and implicate autophagy modulation as a potential therapeutic strategy for SPG4 and possibly other HSPs. © 2025 International Parkinson and Movement Disorder Society.
2025-08-12 | Genotype-Phenotype Distinctions in Spastic Paraplegia 4 Reveal HDAC6 as a Therapeutic Target.
Spastic Paraplegia 4 (SPG4) is the most prevalent form of Hereditary Spastic Paraplegia (HSP), a neurodegenerative disorder characterized by progressive lower limb spasticity and debilitating gait impairment, primarily driven by axonal degeneration of corticospinal motor neurons (CSMNs). Caused by mutations in the SPAST gene encoding spastin, an AAA-ATPase involved in microtubule severing and intracellular organelle function, SPG4 accounts for 40-50% of autosomal dominant HSP cases, yet without effective treatments. Although reduced microtubule acetylation has emerged as a key pathological mechanism, whether and how distinct mutations lead to microtubule deacetylation and subsequent neurodegeneration remains unclear. To address this, we generated isogenic human induced pluripotent stem cell (hiPSC) lines with two distinct heterozygous SPAST mutations - SPAST WT/C448Y (missense) and SPAST WT/S245X (truncation). Employing an innovative differentiation protocol, we created human motor cortical organoids enriched in CSMNs, providing a robust platform to study SPG4 pathophysiology. These organoids revealed striking genotype-phenotype distinctions, with mutation-specific variations in CSMN loss, axonal degeneration and neuronal activities, mirroring clinical heterogeneity. Mechanistic studies identified aberrant activation of histone deacetylase 6 (HDAC6), a major neuronal microtubule deacetylase, as a key driver of SPG4 pathology. This dysregulation was specifically attributed to mutant M1-spastin, the longer isoform of spastin. Remarkably, pharmacological inhibition of HDAC6 with Tubastatin A restored microtubule acetylation status and mitigated axonal degeneration in both SPAST-mutant organoids, with corresponding improvements in corticospinal tract integrity and gait deficits validated in SPG4-transgenic mice. Collectively, our study establishes isogenic hiPSC-derived motor cortical organoids as a robust human model for corticospinal motor neuron degeneration and identifies HDAC6 hyperactivation as a central pathogenic mechanism and viable therapeutic target in SPG4.
proteins
2024-11-30 | Unraveling Isoform Complexity: The Roles of M1- and M87-Spastin in Spastic Paraplegia 4 (SPG4).
Spastic Paraplegia 4 (SPG4) is a debilitating neurodegenerative disorder characterized by progressive muscle weakness and spasticity in the lower limbs, often leading to gait impairment. Central to SPG4 pathology is the die-back degeneration of corticospinal tracts, primarily driven by mutations in the spastin protein encoded by the SPAST gene. SPAST gives rise to two major spastin isoforms, M1- and M87-spastin, which are generated from distinct translation initiation sites. Although spastin is implicated in various cellular functions, the specific roles of each isoform in the pathogenesis of SPG4 remain poorly understood. This review offers an overview of the genetic and structural organization of the M1- and M87-spastin isoforms, highlighting their distinct and overlapping functions, and exploring their potential roles in the haploinsufficiency and gain-of-toxicity mechanisms underlying SPG4. We also present a novel perspective on the evolutionary emergence of M1-spastin and its potential unique involvement in the pathogenesis of SPG4. Drawing upon the latest research, we propose an intriguing hypothesis regarding the hetero-oligomerization of M1- and M87-spastin, exploring how their interaction may drive disease progression and open new avenues for therapeutic intervention. By integrating the current research with these fresh insights, we seek to illuminate the complex molecular mechanisms driving SPG4 and foster the development of innovative therapeutic strategies. This review not only incorporates existing knowledge but also lays the groundwork for future studies aimed at uncovering the isoform-specific roles of spastin in SPG4, with the ultimate goal of advancing targeted treatments for this challenging neurodegenerative disorder. © 2024 International Parkinson and Movement Disorder Society.
2014-12-03 | Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients' neurons.
The hereditary spastic paraplegias (HSPs) are a heterogeneous group of motorneuron diseases characterized by progressive spasticity and paresis of the lower limbs. Mutations in Spastic Gait 4 (SPG4), encoding spastin, are the most frequent cause of HSP. To understand how mutations in SPG4 affect human neurons, we generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of two patients carrying a c.1684C>T nonsense mutation and from two controls. These SPG4 and control hiPSCs were able to differentiate into neurons and glia at comparable efficiency. All known spastin isoforms were reduced in SPG4 neuronal cells. The complexity of SPG4 neurites was decreased, which was paralleled by an imbalance of axonal transport with less retrograde movement. Prominent neurite swellings with disrupted microtubules were present in SPG4 neurons at an ultrastructural level. While some of these swellings contain acetylated and detyrosinated tubulin, these tubulin modifications were unchanged in total cell lysates of SPG4 neurons. Upregulation of another microtubule-severing protein, p60 katanin, may partially compensate for microtubuli dynamics in SPG4 neurons. Overexpression of the M1 or M87 spastin isoforms restored neurite length, branching, numbers of primary neurites and reduced swellings in SPG4 neuronal cells. We conclude that neurite complexity and maintenance in HSP patient-derived neurons are critically sensitive to spastin gene dosage. Our data show that elevation of single spastin isoform levels is sufficient to restore neurite complexity and reduce neurite swellings in patient cells. Furthermore, our human model offers an ideal platform for pharmacological screenings with the goal to restore physiological spastin levels in SPG4 patients.
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.
2026-03-09 | Spastin Is Required to Prevent SPAST-Related Demyelination.
Mutations in the SPAST gene, encoding the microtubule-severing protein Spastin, cause the most common type of hereditary spastic paraplegia (HSP): SPG4, a disorder primarily characterized by length-dependent axonal degeneration. Clinically, most SPG4 patients present with a pure phenotype marked by progressive spasticity in the lower extremities. It has also been reported that complex cases exhibit demyelination and cognitive deficits. Additionally, some SPAST variants have been determined in patients with multiple sclerosis (MS), indicating potential shared pathological mechanisms. Spastin is known to promote axonal regeneration by remodeling microtubules, whereas mutant Spastin disrupts microtubule dynamics and causes axonal transport defects in SPG4. However, whether Spastin dysfunction impairs regenerative processes such as myelination remains unknown. In this study, we investigated whether the SPG4-associated SPAST mutations affect axonal myelination. Using an in vitro cortical neuron-oligodendrocyte co-culture model, we found that pathogenic SPAST mutations result in a significant reduction in the myelination index. Furthermore, a cuprizone-induced demyelination mouse model revealed a decrease in Spastin protein levels in demyelinated white matter. Given Spastin's role in axonal regeneration, we hypothesized that Spastin may also protect against demyelination. Supporting this, wild-type Spastin expression protected neurons from demyelination in a cuprizone-induced cell culture demyelination model. Together, these results suggest a role for Spastin in axonal myelination, and its dysfunction may compromise myelin stability. Our findings highlight that impaired myelin stability may represent a secondary pathological feature of SPG4, contributing to disease complexity. This dual role of Spastin in axonal maintenance and myelin stability suggests its potential relevance for contributing to complex forms of SPG4.
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.
2026-02-25 | MDSGene Systematic Review of Common Forms of Dominant Hereditary Spastic Paraplegia: Novel Insights.
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by progressive spasticity and lower limb weakness. The most common forms of autosomal dominant HSP are caused by pathogenic variants in SPAST (SPG4 or HSP-SPAST), ATL1 (SPG3A or HSP-ATL1), and REEP1 (SPG31 or HSP-REEP1). We performed an MDSGene Systematic Review to determine in-depth genotype-phenotype associations and to estimate longitudinal progression, to inform prognostication and clinical trial stratification. We systematically collected demographic, phenotypic, and genetic data from published reports of individuals affected by these forms of HSP using the MDSGene protocol. We reviewed 2177 affected individuals, including 1670 individuals with HSP-SPAST, 356 with HSP-ATL1 and 151 with HSP-REEP1. HSP-ATL1 was associated with an earlier age at onset compared to HSP-SPAST and HSP-REEP1. Toe-walking was more frequently reported in HSP-ATL1 (10.4%) and HSP-REEP1 (3.3%) than HSP-SPAST (0.3%). Upper limb hyperreflexia and abnormalities of bladder function were more frequent in HSP-SPAST than HSP-ATL1 or HSP-REEP1. Sufficient data was available to estimate disease progression for HSP-SPAST; this showed that Spastic Paraplegia Rating Scale (SPRS) scores increased with increasing age at examination after the age of 40 years. Truncating variants were more frequent in HSP-SPAST and HSP-REEP1 than HSP-ATL1. Overall, HSP-ATL1, HSP-SPAST and HSP-REEP1 demonstrated differences in clinical phenotypes. To our knowledge, this is the first systematic review to model longitudinal progression using SPRS scores in HSP. Missing data is a limiting factor in all these comparisons, highlighting the need for uniform data collection. Online resources can be found at https://www.mdsgene.org/.
2026-02-16 | Two pathogenetic intronic variants in SPG4/SPAST and expansion of the clinical presentation.
Hereditary Spastic Paraplegia (HSP) is a group of inherited neurodegenerative disorders primarily characterized by progressive lower limb spasticity and weakness. Among the various genetic causes of HSP, pathogenetic variants in SPG4/SPAST are the most frequently identified, making them the leading molecular cause of autosomal dominant HSP. The SPAST gene encodes spastin, a protein involved in microtubule dynamics. In this study, we focused on the functional characterization of two specific intronic variants in SPAST absent or present at a very low frequency in GnomAD database and with conflicting classification of pathogenicity, c.1245 + 5G > A and c.1493 + 2_1493 + 5del respectively. These variants were identified in two independent families, one of Brazilian origin and the other of Japanese descent. Our data shows that the splicing variants impact splicing. Furthermore, through segregation analysis and clinical assessments, we provided a detailed description of the affected individuals, emphasizing the clinical presentation associated with these genetic changes. Notably, in both families, the identified variants co-segregated symptoms consistent with anorexia nervosa, suggesting a potential, previously unrecognized association between SPAST pathogenic variants and disordered eating behaviors. Our findings contributed to the expanding clinical spectrum of SPG4-associated HSP and highlighted the importance of characterizing intronic SPAST variants. The characterization of intronic pathogenetic variants enhanced our understanding of their potential pathogenic mechanisms, which may have implications for both genetic diagnosis and the broader clinical management of HSP.
cell therapies
2022-10-24 | Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia
Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders, characterized by progressive lower limb spasticity and weakness resulting from retrograde axonal degeneration of motor neurons (MNs). Here, we generated in vitro human neuromuscular junctions (NMJs) from five HSP patient-specific induced pluripotent stem cell (hiPSC) lines, by means of microfluidic strategy, to model disease-relevant neuropathologic processes. The strength of our NMJ model lies in the generation of lower MNs and myotubes from autologous hiPSC origin, maintaining the genetic background of the HSP patient donors in both cell types and in the cellular organization due to the microfluidic devices. Three patients characterized by a mutation in the SPG3a gene, encoding the ATLASTIN GTPase 1 protein, and two patients with a mutation in the SPG4 gene, encoding the SPASTIN protein, were included in this study. Differentiation of the HSP-derived lines gave rise to lower MNs that could recapitulate pathological hallmarks, such as axonal swellings with accumulation of Acetyl-α-TUBULIN and reduction of SPASTIN levels. Furthermore, NMJs from HSP-derived lines were lower in number and in contact point complexity, denoting an impaired NMJ profile, also confirmed by some alterations in genes encoding for proteins associated with microtubules and responsible for axonal transport. Considering the complexity of HSP, these patient-derived neuronal and skeletal muscle cell co-cultures offer unique tools to study the pathologic mechanisms and explore novel treatment options for rescuing axonal defects and diverse cellular processes, including membrane trafficking, intracellular motility and protein degradation in HSP.
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