RARE DISEASE
Dentatorubral pallidoluysian atrophy
Dentatorubral pallidoluysian atrophy
Dentatorubral pallidoluysian atrophy
Synonyms: DRPLA, Dentatorubropallidoluysian atrophy, Naito-Oyanagi disease
Synonyms: DRPLA, Dentatorubropallidoluysian atrophy, Naito-Oyanagi disease
Synonyms: DRPLA, Dentatorubropallidoluysian atrophy, Naito-Oyanagi disease
Drug discovery
0
drugs
With orphan designations
Overview
Dentatorubral pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the ATN1 gene, leading to neuronal accumulation of mutant atrophin-1 protein. It manifests with ataxia, choreoathetosis, dementia, myoclonus, and seizures, with phenotypic variability based on age of onset (juvenile forms show severe epilepsy, adult-onset cases present with movement disorders). MRI reveals cerebellar/brainstem atrophy, and diagnosis is confirmed genetically [1][2][4][11].
Population
Predominantly affects Japanese populations (prevalence: 0.2–0.7/100,000) but occurs globally, including rare cases in Europe and North America (e.g., Haw River syndrome) [4][9][14].
Anticipation is prominent, particularly with paternal transmission, correlating CAG repeat length with earlier onset and severity [1][4][11].
Burden
Rapid progression (mean survival: ~13 years), with mortality often due to aspiration pneumonia [11][14].
Severe functional decline necessitates intensive caregiver support, while psychiatric symptoms and dementia significantly impact quality of life [4][8][12].
Ultra-rare status complicates clinical trial enrollment, though patient organizations like CureDRPLA drive research and global registry efforts [3][15].
Therapies
Symptomatic management: Antiepileptics (valproate, levetiracetam) for seizures, antipsychotics (quetiapine) for psychosis, and botulinum toxin for focal dystonia [5][12].
Supportive care: Multidisciplinary approaches including physiotherapy, speech therapy, and dysphagia management to reduce complications [5][16].
Emerging therapies: Antisense oligonucleotides (ASOs) targeting ATN1 mRNA are in preclinical trials, leveraging strategies from Huntington’s disease research [3][8][15].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
75 drug discovery papers about Dentatorubral pallidoluysian atrophy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
75 drug discovery papers about Dentatorubral pallidoluysian atrophy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
oligonucleotides
2026-05-14 | CAG-targeting artificial miRNA with reduced off-target risk for efficient lowering of pathogenic polyglutamine proteins.
Huntington's disease (HD) is the best-known example of a neurodegenerative disorder caused by the expansion of a glutamine-encoding CAG repeat in the causative gene. Growing evidence indicates that somatic CAG expansions play a key role in disease progression, providing a strong rationale for therapeutic strategies directly targeting the repeat tract. However, achieving sufficient efficacy while maintaining allele selectivity and minimizing off-target effects remains a major challenge. Here, we developed allele-selective, CAG-targeting artificial microRNA (amiRNA) molecules that exhibit significantly reduced off-target risk. This was achieved by introducing specific substitutions at selected positions within the guide strand. These molecules effectively downregulated polyglutamine (polyQ) proteins in cellular models of HD, spinocerebellar ataxias types 1 and 3, and dentatorubral pallidoluysian atrophy. The most promising candidate, amiR136-13A, reduced mutant huntingtin levels in different brain regions of the HD mouse model and did not induce toxicity up to 28 weeks following a single administration of an AAV5 vector. Transcriptomic profiling of human HD neural stem cells treated with amiR136-13A revealed minor changes in gene expression. Moreover, amiR136-13A reduced the level of HTT1a, a short pathogenic isoform of huntingtin. Collectively, these findings identify amiR136-13A as a potent, selective, and safe therapeutic candidate for HD and potentially other polyQ disorders.
2026-01-13 | Data in support of: Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model
Dentatorubral-pallidoluysian atrophy (DRPLA) is a fatal neurodegenerative disease arising from a CAG repeat expansion in the atrophin-1 (ATN1) gene. Because DRPLA, like many repeat expansion disorders (REDs), arises predominantly from toxic gain-of-function mechanisms, we hypothesized that ATN1 knockdown would have therapeutic potential. To test this, we established the first fully humanized mouse model of a RED, in which one allele of mouse Atn1 is completely replaced by human ATN1, including 112 pure CAG repeats. This novel approach to exploring RED biology provides significant advantages, notably the ability to test sequence-specific therapeutics targeting human sequences, even in introns and untranslated regions of pre-mRNA. We found that our model—the Atn1Q112/+ mouse—recapitulates key features of human DRPLA, including behavioral alterations, reduced brain size, and aggregate accumulation. We treated Atn1Q112/+ mice with antisense oligonucleotides (ASOs) targeting mouse Atn1 (to probe for loss of function concerns), human ATN1, or a combination. Treatment with human, but not mouse, ATN1-targeting ASOs provides remarkable protection from a range of disease-related behavioral phenotypes and marked rescue of transcriptional dysregulation in the cerebellum. These results have helped motivate an ongoing human clinical study of ASOs targeting ATN1 for DRPLA.
2025-03-18 | Atrophin-1 Antisense Oligonucleotide Provides Robust Protection from Pathology in a Fully Humanized DRPLA Model
Dentatorubral-pallidoluysian atrophy (DRPLA) is a fatal neurodegenerative disease arising from a CAG repeat expansion in the atrophin-1 (ATN1) gene. Because DRPLA, like many repeat expansion disorders (REDs), arises predominantly from toxic gain-of-function mechanisms, we hypothesized that ATN1 knockdown would have therapeutic potential. To test this, we established the first fully-humanized mouse model of a RED, in which one allele of mouse Atn1 is completely replaced by human ATN1, including 112 pure CAG repeats. This novel approach to exploring RED biology provides significant advantages, notably the ability to test sequence-specific therapeutics targeting human sequences, even in introns and untranslated regions of pre-mRNA. We found that our model, the Atn1Q112/+ mouse, recapitulates key features of human DRPLA, including behavioral alterations, reduced brain size and aggregate accumulation. We treated Atn1Q112/+ mice with antisense oligonucleotides (ASOs) targeting mouse Atn1 (to probe for loss of function concerns), human ATN1, or a combination. Treatment with human, but not mouse, ATN1-targeting ASOs provides remarkable protection from a range of disease-related behavioral phenotypes, including aggregation of mutant ATN1 (mATN1), and marked rescue of transcriptional dysregulation in the cerebellum. These results have helped motivate an ongoing human clinical study of ASOs targeting ATN1 for DRPLA.
2021-07-21 | DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder.
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene and is inherited in an autosomal dominant fashion. There are currently no disease-modifying treatments available. The broad development of therapies for DRPLA, as well as other similar rare diseases, has hit a roadblock due to the rarity of the condition and the wide global distribution of patients and families, consequently inhibiting biomarker development and therapeutic research. Considering the shifting focus towards diverse populations, widespread genetic testing, rapid advancements in the development of clinical and wet biomarkers for Huntington's disease (HD), and the ongoing clinical trials for antisense oligonucleotide (ASO) therapies, the prospect of developing effective treatments in rare disorders has completely changed. The awareness of the HD ASO program has prompted global collaboration for rare disorders in natural history studies and the development of biomarkers, with the eventual goal of undergoing treatment trials. Here, we discuss DRPLA, which shares similarities with HD, and how in this and other repeat expansion disorders, neurogenetics groups like ours at UCL are gearing up for forthcoming natural history studies to accelerate future ASO treatment trials to hopefully emulate the progress seen in HD.
2021-02-12 | Protein Aggregation Inhibitors as Disease-Modifying Therapies for Polyglutamine Diseases
The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases caused by the abnormal expansion of a CAG trinucleotide repeat that are translated into an expanded polyQ stretch in the disease-causative proteins. The expanded polyQ stretch itself plays a critical disease-causative role in the pathomechanisms underlying polyQ diseases. Notably, the expanded polyQ stretch undergoes a conformational transition from the native monomer into the β-sheet-rich monomer, followed by the formation of soluble oligomers and then insoluble aggregates with amyloid fibrillar structures. The intermediate soluble species including the β-sheet-rich monomer and oligomers exhibit substantial neurotoxicity. Therefore, protein conformation stabilization and aggregation inhibition that target the upstream of the insoluble aggregate formation would be a promising approach toward the development of disease-modifying therapies for polyQ diseases. PolyQ aggregation inhibitors of different chemical categories, such as intrabodies, peptides, and small chemical compounds, have been identified through intensive screening methods. Among them, recent advances in the brain delivery methods of several peptides and the screening of small chemical compounds have brought them closer to clinical utility. Notably, the recent discovery of arginine as a potent conformation stabilizer and aggregation inhibitor of polyQ proteins both in vitro and in vivo have paved way to the clinical trial for the patients with polyQ diseases. Meanwhile, expression reduction of expanded polyQ proteins per se would be another promising approach toward disease modification of polyQ diseases. Gene silencing, especially by antisense oligonucleotides (ASOs), have succeeded in reducing the expression of polyQ proteins in the animal models of various polyQ diseases by targeting the aberrant mRNA with expanded CAG repeats. Of note, some of these ASOs have recently been translated into clinical trials. Here we overview and discuss these recent advances toward the development of disease modifying therapies for polyQ diseases. We envision that combination therapies using aggregation inhibitors and gene silencing would meet the needs of the patients with polyQ diseases and their caregivers in the near future to delay or prevent the onset and progression of these currently intractable diseases.
small molecules
2026-02-22 | Long-term efficacy and disease-specific responsiveness to protirelin in patients with spinocerebellar degeneration: A retrospective study.
The thyrotropin-releasing hormone (TRH) analog protirelin has short-term benefits for cerebellar ataxia (CA), but its long-term efficacy and the subtype-specific responsiveness of spinocerebellar degeneration (SCD) patients remain unclear. We retrospectively reviewed the records of 92 SCD patients (273 courses) treated with protirelin between July 2011 and October 2025, including patients with idiopathic CA (IDCA), multiple system atrophy with predominant CA (MSA-C) or parkinsonism (MSA-P), and genetic subtypes including spinocerebellar ataxia (SCA) type 6, SCA31 and dentatorubral-pallidoluysian atrophy (DRPLA). Responders were defined as showing ≥1-point improvement on the Scale for the Assessment and Rating of Ataxia (SARA). Protirelin was effective in 64.1% of subjects, with significant improvement overall (p < 0.001) and significant SARA gains in MSA-C (p = 0.047), IDCA (p = 0.02), and SCA31 (p = 0.01). Change in SARA score (ΔSARA) correlated negatively with age and positively with total protirelin dose in IDCA, and negatively with age and disease duration and positively with baseline SARA score in SCA31. Several IDCA and DRPLA patients maintained clinical benefit for more than 10 years. All MSA-P discontinued protirelin within 2 years and all MSA-C within 5 years; some SCA6, and SCA31 patients continued for ≥5 years. Adverse effects were infrequent (2/92, 2.2%). Protirelin is efficacious in SCD patients and well-tolerated, particularly in slow-progressing phenotypes (IDCA and SCA31); its benefit in rapidly progressing ataxias (MSA-C) may be confined to early disease stages. Prospective studies with standardized dosing and long-term follow-up are warranted to establish evidence-based protocols for TRH-related therapy for CA.
2025-11-27 | ERBB4 colocalizes with phosphorylated tau aggregates in multiple tauopathies.
The neuregulin-ERBB4 pathway is essential for maintaining cellular function. Upon stimulation by its ligand, neuregulin, ERBB4-a receptor tyrosine kinase-triggers multiple cellular responses, including proliferation, apoptosis, differentiation, and neuromuscular junction formation. Previous research has implicated dysregulated ERBB4 signaling in the pathophysiology of several neurodegenerative disorders, such as Alzheimer's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, and Parkinson's disease. In this study, we examined ERBB4 expression in diseases characterized by phosphorylated tau (MAPT) pathology. We found that ERBB4 colocalized with neuronal and glial phosphorylated tau-positive inclusions in multiple tauopathies, including Pick's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutation. Conversely, ERBB4 did not colocalize with α-synuclein aggregates in α-synucleinopathies (Parkinson's disease and multiple system atrophy) or with neuronal intranuclear inclusions in triplet repeat disorders (Huntington's disease and dentatorubral-pallidoluysian atrophy). A co-immunoprecipitation assay indicated that ERBB4 can interact with tau intracellularly. Notably, in corticobasal degeneration, we observed ectopic ERBB4 expression in astrocytes lacking apparent phosphorylated tau aggregates. These findings suggest a potential role for ERBB4 in the pathophysiology of tau-related neurodegenerative diseases.
2025-09-07 | Mitochondrial dysfunction precedes neurodegeneration in DRPLA patient-derived neurons, and phenylbutyrate improves survival
Abstract Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion in the ATN1 gene, which encodes the transcriptional corepressor Atrophin-1. The temporal sequence of molecular mechanisms driving neuronal dysfunction and degeneration in DRPLA is poorly understood, limiting therapeutic development. We generated patient-derived induced pluripotent stem cells and differentiated them into cortical excitatory glutamatergic neurons to model early pathogenic processes. Early pathological features of DRPLA patient-derived neurons included mitochondrial dysfunction and oxidative stress. These alterations occurred before overt neuronal loss, highlighting bioenergetic stress as a key early driver of disease progression toward neurodegeneration. Pharmacological treatment with phenylbutyrate significantly improved neuronal survival and reduced mitochondrial reactive oxygen species production, demonstrating the therapeutic potential of targeting mitochondrial dysfunction and oxidative stress. These findings challenge the conventional aggregation-centric model of polyglutamine disease pathogenesis and position mitochondrial stress as a central and early promoter of neuronal degeneration in DRPLA. By providing mechanistic insight into early-stage disease processes, our study lays the foundation for therapeutic strategies targeting mitochondrial dysfunction in DRPLA and related polyglutamine disorders.
2025-07-01 | Intrathecal baclofen therapy can improve spasticity associated with infantile-onset dentatorubral-pallidoluysian atrophy: illustrative cases.
In this study, the authors aimed to investigate the efficacy of intrathecal baclofen (ITB) therapy in alleviating intractable spasticity in patients with infantile-onset dentatorubral-pallidoluysian atrophy (DRPLA). Given the lack of effective treatments for the severe spasticity observed in infantile-onset DRPLA patients, this study explored ITB therapy as a potential therapeutic strategy. The authors included 3 patients (2 males and 1 female, aged 9-24 years) diagnosed with infantile-onset DRPLA who underwent ITB pump implantation. All patients exhibited severe spasticity unresponsive to conventional treatments. Patient demographics, clinical history, cytosine-adenine-guanine repeat number, radiological findings, and symptomatic improvements after ITB therapy were recorded and analyzed. The 3 patients demonstrated marked improvement in spasticity following ITB therapy, with significant reductions in modified Ashworth scale score and alleviation of pain, facilitating easier care and improving quality of life. Improvements were also noted in paroxysmal hypertonia frequency, sleep disturbances, and emaciation. ITB therapy significantly reduced intractable spasticity and associated symptoms in patients with infantile-onset DRPLA, offering a promising therapeutic option for this patient population. Further studies are warranted to explore the long-term efficacy and safety of ITB therapy in a larger cohort of DRPLA patients. https://thejns.org/doi/10.3171/CASE24784.
2025-06-01 | Accurate Quantification of Mutant and Wild-Type polyQ Proteins Using Simple Western Capillary Immunoassays.
Polyglutamine (polyQ) diseases are monogenic fatal neurodegenerative disorders caused by a CAG repeat expansion that is translated into a toxic polyQ tract. There are nine polyQ diseases: Huntington's disease (HD), spinocerebellar ataxias 1, 2, 3, 6, 7 and 17 (SCA1, 2, 3, 6, 7, 17), dentatorubral-pallidoluysian atrophy (DRPLA) and spinal and bulbar muscular atrophy (SBMA). Although no disease-modifying therapies are available, lowering levels of the causative mutant polyQ protein is a promising potential treatment. Preclinically, the efficacy of polyQ protein-lowering compounds is often assessed using time-consuming Western blots (WB), which can produce variable results. Therefore, to improve throughput and accuracy of polyQ protein level quantification, Simple Western (SW) capillary immunoassays were developed. A panel of antibodies was screened for reactivity to the polyQ proteins on SW. The most promising antibodies were selected for further assay development. This resulted in optimised SW immunoassays for huntingtin (HTT), ataxin 1, 2 and 3 (ATXN1, 2, 3), atrophin 1 (ATN1) and androgen receptor (AR). Additionally, size-separation of the wild-type and polyQ-expanded mutant protein isoforms on SW was shown for ATXN1, ATXN3 and ATN1, allowing for their separate quantification. To facilitate size-separation of the larger HTT protein (≥ 348 kDa), a novel caspase 3-based assay was developed to generate N-terminal wild-type and mutant HTT fragments that could be separately quantified on SW in contrast to full-length HTT. In conclusion, SW capillary immunoassays were developed for polyQ proteins to improve preclinical research and aid the development of polyQ-lowering therapies for polyQ diseases.
proteins
2024-07-25 | Peptide Based Therapy for Neurological Disorders.
Peptides are small molecules composed of amino acids linked together by peptide bonds. The targeted action of these peptides along with their magnificent ability to reach locations in the body that are complicated to access, is being considered of tremendous potential in disease modifying therapies. Synthetic as well as natural peptides like Carnosine are currently under research for the treatment of Neurodegenerative Disorders (NDDs). Peptide based vaccines are currently under immense research for diseases like dementia. Toxicity of peptide-based drugs towards eukaryotic cells due to their increased haemolytic activity is of major concern and this is being tackled by introducing modifications into the peptide structure. Some crucial peptide inhibitors currently in use for neurodegenerative disorders include Aβ (16-20) KLVFF for Alzheimer's disease, NAPVSIPQ (NAP) for Parkinson's disease, towards eukaryotic cells Vasoactive Intestinal Peptides (VIP) for Huntington's disease, Polyglutamine Binding Peptide-1(QBP1) for Dentatorubral- pallidoluysian atrophy (DRPLA). Certain peptides are involved in inhibition of Mitochondrial Permeability Transition (MPT) that plays a prominent part in the materialization of neurodegenerative diseases, one such example of peptides being Ba-V which is obtained from Bothrops atrox snake venom. New therapeutic peptides are being identified using bioinformatics tools like High Throughput Screening (HTS). These tools are being used to explore the selectivity, stability, extent of immune response and toxic side effects of peptides. Apart from neurodegenerative diseases, the potential of bioactive peptides is also being tested against cancer, diabetes and microbes. This review focuses on the recent advances in peptide therapeutics and novel peptides discovered for the treatment of NDs.
2005-09-12 | Characterization of a possible amyloidogenic precursor in glutamine-repeat neurodegenerative diseases
Several neurodegenerative diseases are linked to expanded repeats of glutamine residues, which lead to the formation of amyloid fibrils and neuronal death. The length of the repeats correlates with the onset of Huntington's disease, such that healthy individuals have <38 residues and individuals with >38 repeats exhibit symptoms. Because it is difficult to obtain atomic-resolution structural information for poly( l -glutamine) (polyQ) in aqueous solution experimentally, we performed molecular dynamics simulations to investigate the conformational behavior of this homopolymer. In simulations of 20-, 40-, and 80-mer polyQ, we observed the formation of the “α-extended chain” conformation, which is characterized by alternating residues in the α L and α R conformations to yield a sheet. The structural transition from disordered random-coil conformations to the α-extended chain conformation exhibits modest length and temperature dependence, in agreement with the experimental observation that aggregation depends on length and temperature. We propose that fibril formation in polyQ may occur through an α-sheet structure, which was proposed by Pauling and Corey [Pauling, L. & Corey, R. B. (1951) Proc. Natl. Acad. Sci. USA 37, 251-256]. Also, we propose an atomic-resolution model of how the inhibitory peptide QBP1 (polyQ-binding peptide 1) may bind to polyQ in an α-extended chain conformation to inhibit fibril formation.
2005-07-25 | Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches.
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal-dominant neurodegenerative disorder caused by expansion of CAG repeats in the DRPLA gene, which codes for a polyglutamine (polyQ) stretch. The expanded polyQs are known to form intracellular aggregates and to confer neurotoxic activity. Recent studies have indicated that activation of apoptosis signal-regulating kinase 1 (ASK1) is involved in polyQ-induced apoptosis. Humanin (HN) is an endogenous peptide that inhibits neuronal cell death caused by mutant Alzheimer's disease genes, and this neuroprotective factor has recently been reported to suppress apoptosis by inhibiting activation of ASK1. To test the anti-ASK1 effect of HN on polyQ neurotoxicity, we constructed neuronal PC12 cells expressing expanded polyQs under the control of the Tet-Off system. Using this cell line, we showed that HN suppresses apoptotic cell death induced by expanded polyQs. However, the suppression was incomplete, suggesting that polyQs also stimulate other pathogenic cascades unrelated to ASK1. We further showed that HN suppresses polyQ aggregate formation. This result implied the possibility that aggregation is also related to the polyQ-mediated cascade involving ASK1 activation. Although the details remain uncertain, our results suggest that ASK1 is potentially involved in pathogenesis of DRPLA and that HN might contribute partially to the suppression of neurodegeneration in polyQ diseases.
oligonucleotides
2026-05-14 | CAG-targeting artificial miRNA with reduced off-target risk for efficient lowering of pathogenic polyglutamine proteins.
Huntington's disease (HD) is the best-known example of a neurodegenerative disorder caused by the expansion of a glutamine-encoding CAG repeat in the causative gene. Growing evidence indicates that somatic CAG expansions play a key role in disease progression, providing a strong rationale for therapeutic strategies directly targeting the repeat tract. However, achieving sufficient efficacy while maintaining allele selectivity and minimizing off-target effects remains a major challenge. Here, we developed allele-selective, CAG-targeting artificial microRNA (amiRNA) molecules that exhibit significantly reduced off-target risk. This was achieved by introducing specific substitutions at selected positions within the guide strand. These molecules effectively downregulated polyglutamine (polyQ) proteins in cellular models of HD, spinocerebellar ataxias types 1 and 3, and dentatorubral pallidoluysian atrophy. The most promising candidate, amiR136-13A, reduced mutant huntingtin levels in different brain regions of the HD mouse model and did not induce toxicity up to 28 weeks following a single administration of an AAV5 vector. Transcriptomic profiling of human HD neural stem cells treated with amiR136-13A revealed minor changes in gene expression. Moreover, amiR136-13A reduced the level of HTT1a, a short pathogenic isoform of huntingtin. Collectively, these findings identify amiR136-13A as a potent, selective, and safe therapeutic candidate for HD and potentially other polyQ disorders.
2026-01-13 | Data in support of: Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model
Dentatorubral-pallidoluysian atrophy (DRPLA) is a fatal neurodegenerative disease arising from a CAG repeat expansion in the atrophin-1 (ATN1) gene. Because DRPLA, like many repeat expansion disorders (REDs), arises predominantly from toxic gain-of-function mechanisms, we hypothesized that ATN1 knockdown would have therapeutic potential. To test this, we established the first fully humanized mouse model of a RED, in which one allele of mouse Atn1 is completely replaced by human ATN1, including 112 pure CAG repeats. This novel approach to exploring RED biology provides significant advantages, notably the ability to test sequence-specific therapeutics targeting human sequences, even in introns and untranslated regions of pre-mRNA. We found that our model—the Atn1Q112/+ mouse—recapitulates key features of human DRPLA, including behavioral alterations, reduced brain size, and aggregate accumulation. We treated Atn1Q112/+ mice with antisense oligonucleotides (ASOs) targeting mouse Atn1 (to probe for loss of function concerns), human ATN1, or a combination. Treatment with human, but not mouse, ATN1-targeting ASOs provides remarkable protection from a range of disease-related behavioral phenotypes and marked rescue of transcriptional dysregulation in the cerebellum. These results have helped motivate an ongoing human clinical study of ASOs targeting ATN1 for DRPLA.
2025-03-18 | Atrophin-1 Antisense Oligonucleotide Provides Robust Protection from Pathology in a Fully Humanized DRPLA Model
Dentatorubral-pallidoluysian atrophy (DRPLA) is a fatal neurodegenerative disease arising from a CAG repeat expansion in the atrophin-1 (ATN1) gene. Because DRPLA, like many repeat expansion disorders (REDs), arises predominantly from toxic gain-of-function mechanisms, we hypothesized that ATN1 knockdown would have therapeutic potential. To test this, we established the first fully-humanized mouse model of a RED, in which one allele of mouse Atn1 is completely replaced by human ATN1, including 112 pure CAG repeats. This novel approach to exploring RED biology provides significant advantages, notably the ability to test sequence-specific therapeutics targeting human sequences, even in introns and untranslated regions of pre-mRNA. We found that our model, the Atn1Q112/+ mouse, recapitulates key features of human DRPLA, including behavioral alterations, reduced brain size and aggregate accumulation. We treated Atn1Q112/+ mice with antisense oligonucleotides (ASOs) targeting mouse Atn1 (to probe for loss of function concerns), human ATN1, or a combination. Treatment with human, but not mouse, ATN1-targeting ASOs provides remarkable protection from a range of disease-related behavioral phenotypes, including aggregation of mutant ATN1 (mATN1), and marked rescue of transcriptional dysregulation in the cerebellum. These results have helped motivate an ongoing human clinical study of ASOs targeting ATN1 for DRPLA.
2021-07-21 | DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder.
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene and is inherited in an autosomal dominant fashion. There are currently no disease-modifying treatments available. The broad development of therapies for DRPLA, as well as other similar rare diseases, has hit a roadblock due to the rarity of the condition and the wide global distribution of patients and families, consequently inhibiting biomarker development and therapeutic research. Considering the shifting focus towards diverse populations, widespread genetic testing, rapid advancements in the development of clinical and wet biomarkers for Huntington's disease (HD), and the ongoing clinical trials for antisense oligonucleotide (ASO) therapies, the prospect of developing effective treatments in rare disorders has completely changed. The awareness of the HD ASO program has prompted global collaboration for rare disorders in natural history studies and the development of biomarkers, with the eventual goal of undergoing treatment trials. Here, we discuss DRPLA, which shares similarities with HD, and how in this and other repeat expansion disorders, neurogenetics groups like ours at UCL are gearing up for forthcoming natural history studies to accelerate future ASO treatment trials to hopefully emulate the progress seen in HD.
2021-02-12 | Protein Aggregation Inhibitors as Disease-Modifying Therapies for Polyglutamine Diseases
The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases caused by the abnormal expansion of a CAG trinucleotide repeat that are translated into an expanded polyQ stretch in the disease-causative proteins. The expanded polyQ stretch itself plays a critical disease-causative role in the pathomechanisms underlying polyQ diseases. Notably, the expanded polyQ stretch undergoes a conformational transition from the native monomer into the β-sheet-rich monomer, followed by the formation of soluble oligomers and then insoluble aggregates with amyloid fibrillar structures. The intermediate soluble species including the β-sheet-rich monomer and oligomers exhibit substantial neurotoxicity. Therefore, protein conformation stabilization and aggregation inhibition that target the upstream of the insoluble aggregate formation would be a promising approach toward the development of disease-modifying therapies for polyQ diseases. PolyQ aggregation inhibitors of different chemical categories, such as intrabodies, peptides, and small chemical compounds, have been identified through intensive screening methods. Among them, recent advances in the brain delivery methods of several peptides and the screening of small chemical compounds have brought them closer to clinical utility. Notably, the recent discovery of arginine as a potent conformation stabilizer and aggregation inhibitor of polyQ proteins both in vitro and in vivo have paved way to the clinical trial for the patients with polyQ diseases. Meanwhile, expression reduction of expanded polyQ proteins per se would be another promising approach toward disease modification of polyQ diseases. Gene silencing, especially by antisense oligonucleotides (ASOs), have succeeded in reducing the expression of polyQ proteins in the animal models of various polyQ diseases by targeting the aberrant mRNA with expanded CAG repeats. Of note, some of these ASOs have recently been translated into clinical trials. Here we overview and discuss these recent advances toward the development of disease modifying therapies for polyQ diseases. We envision that combination therapies using aggregation inhibitors and gene silencing would meet the needs of the patients with polyQ diseases and their caregivers in the near future to delay or prevent the onset and progression of these currently intractable diseases.
small molecules
2026-02-22 | Long-term efficacy and disease-specific responsiveness to protirelin in patients with spinocerebellar degeneration: A retrospective study.
The thyrotropin-releasing hormone (TRH) analog protirelin has short-term benefits for cerebellar ataxia (CA), but its long-term efficacy and the subtype-specific responsiveness of spinocerebellar degeneration (SCD) patients remain unclear. We retrospectively reviewed the records of 92 SCD patients (273 courses) treated with protirelin between July 2011 and October 2025, including patients with idiopathic CA (IDCA), multiple system atrophy with predominant CA (MSA-C) or parkinsonism (MSA-P), and genetic subtypes including spinocerebellar ataxia (SCA) type 6, SCA31 and dentatorubral-pallidoluysian atrophy (DRPLA). Responders were defined as showing ≥1-point improvement on the Scale for the Assessment and Rating of Ataxia (SARA). Protirelin was effective in 64.1% of subjects, with significant improvement overall (p < 0.001) and significant SARA gains in MSA-C (p = 0.047), IDCA (p = 0.02), and SCA31 (p = 0.01). Change in SARA score (ΔSARA) correlated negatively with age and positively with total protirelin dose in IDCA, and negatively with age and disease duration and positively with baseline SARA score in SCA31. Several IDCA and DRPLA patients maintained clinical benefit for more than 10 years. All MSA-P discontinued protirelin within 2 years and all MSA-C within 5 years; some SCA6, and SCA31 patients continued for ≥5 years. Adverse effects were infrequent (2/92, 2.2%). Protirelin is efficacious in SCD patients and well-tolerated, particularly in slow-progressing phenotypes (IDCA and SCA31); its benefit in rapidly progressing ataxias (MSA-C) may be confined to early disease stages. Prospective studies with standardized dosing and long-term follow-up are warranted to establish evidence-based protocols for TRH-related therapy for CA.
2025-11-27 | ERBB4 colocalizes with phosphorylated tau aggregates in multiple tauopathies.
The neuregulin-ERBB4 pathway is essential for maintaining cellular function. Upon stimulation by its ligand, neuregulin, ERBB4-a receptor tyrosine kinase-triggers multiple cellular responses, including proliferation, apoptosis, differentiation, and neuromuscular junction formation. Previous research has implicated dysregulated ERBB4 signaling in the pathophysiology of several neurodegenerative disorders, such as Alzheimer's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, and Parkinson's disease. In this study, we examined ERBB4 expression in diseases characterized by phosphorylated tau (MAPT) pathology. We found that ERBB4 colocalized with neuronal and glial phosphorylated tau-positive inclusions in multiple tauopathies, including Pick's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutation. Conversely, ERBB4 did not colocalize with α-synuclein aggregates in α-synucleinopathies (Parkinson's disease and multiple system atrophy) or with neuronal intranuclear inclusions in triplet repeat disorders (Huntington's disease and dentatorubral-pallidoluysian atrophy). A co-immunoprecipitation assay indicated that ERBB4 can interact with tau intracellularly. Notably, in corticobasal degeneration, we observed ectopic ERBB4 expression in astrocytes lacking apparent phosphorylated tau aggregates. These findings suggest a potential role for ERBB4 in the pathophysiology of tau-related neurodegenerative diseases.
2025-09-07 | Mitochondrial dysfunction precedes neurodegeneration in DRPLA patient-derived neurons, and phenylbutyrate improves survival
Abstract Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion in the ATN1 gene, which encodes the transcriptional corepressor Atrophin-1. The temporal sequence of molecular mechanisms driving neuronal dysfunction and degeneration in DRPLA is poorly understood, limiting therapeutic development. We generated patient-derived induced pluripotent stem cells and differentiated them into cortical excitatory glutamatergic neurons to model early pathogenic processes. Early pathological features of DRPLA patient-derived neurons included mitochondrial dysfunction and oxidative stress. These alterations occurred before overt neuronal loss, highlighting bioenergetic stress as a key early driver of disease progression toward neurodegeneration. Pharmacological treatment with phenylbutyrate significantly improved neuronal survival and reduced mitochondrial reactive oxygen species production, demonstrating the therapeutic potential of targeting mitochondrial dysfunction and oxidative stress. These findings challenge the conventional aggregation-centric model of polyglutamine disease pathogenesis and position mitochondrial stress as a central and early promoter of neuronal degeneration in DRPLA. By providing mechanistic insight into early-stage disease processes, our study lays the foundation for therapeutic strategies targeting mitochondrial dysfunction in DRPLA and related polyglutamine disorders.
2025-07-01 | Intrathecal baclofen therapy can improve spasticity associated with infantile-onset dentatorubral-pallidoluysian atrophy: illustrative cases.
In this study, the authors aimed to investigate the efficacy of intrathecal baclofen (ITB) therapy in alleviating intractable spasticity in patients with infantile-onset dentatorubral-pallidoluysian atrophy (DRPLA). Given the lack of effective treatments for the severe spasticity observed in infantile-onset DRPLA patients, this study explored ITB therapy as a potential therapeutic strategy. The authors included 3 patients (2 males and 1 female, aged 9-24 years) diagnosed with infantile-onset DRPLA who underwent ITB pump implantation. All patients exhibited severe spasticity unresponsive to conventional treatments. Patient demographics, clinical history, cytosine-adenine-guanine repeat number, radiological findings, and symptomatic improvements after ITB therapy were recorded and analyzed. The 3 patients demonstrated marked improvement in spasticity following ITB therapy, with significant reductions in modified Ashworth scale score and alleviation of pain, facilitating easier care and improving quality of life. Improvements were also noted in paroxysmal hypertonia frequency, sleep disturbances, and emaciation. ITB therapy significantly reduced intractable spasticity and associated symptoms in patients with infantile-onset DRPLA, offering a promising therapeutic option for this patient population. Further studies are warranted to explore the long-term efficacy and safety of ITB therapy in a larger cohort of DRPLA patients. https://thejns.org/doi/10.3171/CASE24784.
2025-06-01 | Accurate Quantification of Mutant and Wild-Type polyQ Proteins Using Simple Western Capillary Immunoassays.
Polyglutamine (polyQ) diseases are monogenic fatal neurodegenerative disorders caused by a CAG repeat expansion that is translated into a toxic polyQ tract. There are nine polyQ diseases: Huntington's disease (HD), spinocerebellar ataxias 1, 2, 3, 6, 7 and 17 (SCA1, 2, 3, 6, 7, 17), dentatorubral-pallidoluysian atrophy (DRPLA) and spinal and bulbar muscular atrophy (SBMA). Although no disease-modifying therapies are available, lowering levels of the causative mutant polyQ protein is a promising potential treatment. Preclinically, the efficacy of polyQ protein-lowering compounds is often assessed using time-consuming Western blots (WB), which can produce variable results. Therefore, to improve throughput and accuracy of polyQ protein level quantification, Simple Western (SW) capillary immunoassays were developed. A panel of antibodies was screened for reactivity to the polyQ proteins on SW. The most promising antibodies were selected for further assay development. This resulted in optimised SW immunoassays for huntingtin (HTT), ataxin 1, 2 and 3 (ATXN1, 2, 3), atrophin 1 (ATN1) and androgen receptor (AR). Additionally, size-separation of the wild-type and polyQ-expanded mutant protein isoforms on SW was shown for ATXN1, ATXN3 and ATN1, allowing for their separate quantification. To facilitate size-separation of the larger HTT protein (≥ 348 kDa), a novel caspase 3-based assay was developed to generate N-terminal wild-type and mutant HTT fragments that could be separately quantified on SW in contrast to full-length HTT. In conclusion, SW capillary immunoassays were developed for polyQ proteins to improve preclinical research and aid the development of polyQ-lowering therapies for polyQ diseases.
proteins
2024-07-25 | Peptide Based Therapy for Neurological Disorders.
Peptides are small molecules composed of amino acids linked together by peptide bonds. The targeted action of these peptides along with their magnificent ability to reach locations in the body that are complicated to access, is being considered of tremendous potential in disease modifying therapies. Synthetic as well as natural peptides like Carnosine are currently under research for the treatment of Neurodegenerative Disorders (NDDs). Peptide based vaccines are currently under immense research for diseases like dementia. Toxicity of peptide-based drugs towards eukaryotic cells due to their increased haemolytic activity is of major concern and this is being tackled by introducing modifications into the peptide structure. Some crucial peptide inhibitors currently in use for neurodegenerative disorders include Aβ (16-20) KLVFF for Alzheimer's disease, NAPVSIPQ (NAP) for Parkinson's disease, towards eukaryotic cells Vasoactive Intestinal Peptides (VIP) for Huntington's disease, Polyglutamine Binding Peptide-1(QBP1) for Dentatorubral- pallidoluysian atrophy (DRPLA). Certain peptides are involved in inhibition of Mitochondrial Permeability Transition (MPT) that plays a prominent part in the materialization of neurodegenerative diseases, one such example of peptides being Ba-V which is obtained from Bothrops atrox snake venom. New therapeutic peptides are being identified using bioinformatics tools like High Throughput Screening (HTS). These tools are being used to explore the selectivity, stability, extent of immune response and toxic side effects of peptides. Apart from neurodegenerative diseases, the potential of bioactive peptides is also being tested against cancer, diabetes and microbes. This review focuses on the recent advances in peptide therapeutics and novel peptides discovered for the treatment of NDs.
2005-09-12 | Characterization of a possible amyloidogenic precursor in glutamine-repeat neurodegenerative diseases
Several neurodegenerative diseases are linked to expanded repeats of glutamine residues, which lead to the formation of amyloid fibrils and neuronal death. The length of the repeats correlates with the onset of Huntington's disease, such that healthy individuals have <38 residues and individuals with >38 repeats exhibit symptoms. Because it is difficult to obtain atomic-resolution structural information for poly( l -glutamine) (polyQ) in aqueous solution experimentally, we performed molecular dynamics simulations to investigate the conformational behavior of this homopolymer. In simulations of 20-, 40-, and 80-mer polyQ, we observed the formation of the “α-extended chain” conformation, which is characterized by alternating residues in the α L and α R conformations to yield a sheet. The structural transition from disordered random-coil conformations to the α-extended chain conformation exhibits modest length and temperature dependence, in agreement with the experimental observation that aggregation depends on length and temperature. We propose that fibril formation in polyQ may occur through an α-sheet structure, which was proposed by Pauling and Corey [Pauling, L. & Corey, R. B. (1951) Proc. Natl. Acad. Sci. USA 37, 251-256]. Also, we propose an atomic-resolution model of how the inhibitory peptide QBP1 (polyQ-binding peptide 1) may bind to polyQ in an α-extended chain conformation to inhibit fibril formation.
2005-07-25 | Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches.
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal-dominant neurodegenerative disorder caused by expansion of CAG repeats in the DRPLA gene, which codes for a polyglutamine (polyQ) stretch. The expanded polyQs are known to form intracellular aggregates and to confer neurotoxic activity. Recent studies have indicated that activation of apoptosis signal-regulating kinase 1 (ASK1) is involved in polyQ-induced apoptosis. Humanin (HN) is an endogenous peptide that inhibits neuronal cell death caused by mutant Alzheimer's disease genes, and this neuroprotective factor has recently been reported to suppress apoptosis by inhibiting activation of ASK1. To test the anti-ASK1 effect of HN on polyQ neurotoxicity, we constructed neuronal PC12 cells expressing expanded polyQs under the control of the Tet-Off system. Using this cell line, we showed that HN suppresses apoptotic cell death induced by expanded polyQs. However, the suppression was incomplete, suggesting that polyQs also stimulate other pathogenic cascades unrelated to ASK1. We further showed that HN suppresses polyQ aggregate formation. This result implied the possibility that aggregation is also related to the polyQ-mediated cascade involving ASK1 activation. Although the details remain uncertain, our results suggest that ASK1 is potentially involved in pathogenesis of DRPLA and that HN might contribute partially to the suppression of neurodegeneration in polyQ diseases.
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