spinocerebellar-ataxia-type-2

Spinocerebellar Ataxia Type 2 (SCA2)

Introduction

Spinocerebellar Ataxia Type 2 (Sca2) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Spinocerebellar Ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia, distinctive oculomotor abnormalities, and variable additional features including peripheral neuropathy and cognitive impairment. It is caused by a CAG trinucleotide repeat expansion in the ATXN2 gene and is one of the most common spinocerebellar ataxias worldwide[@spinocerebellar2008].

Overview

Spinocerebellar Ataxia type 2 is a member of the polyglutamine disease family, sharing pathogenic mechanisms with SCA1, Huntington's Disease, and other trinucleotide repeat disorders. SCA2 was first described as a distinct clinical entity in the late 1980s, and the causative gene (ATXN2) was identified in 1996[@moderate1996].

The prevalence of SCA2 varies geographically, with higher frequencies in populations including those of Cuban, Indian, and Japanese descent. In Cuba, SCA2 accounts for up to 30% of all autosomal dominant cerebellar ataxias, representing the most common SCA in that population[@molecular2006]. The disease typically manifests in the second to fourth decade of life, though juvenile-onset cases occur with larger repeat expansions.

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Spinocerebellar Ataxia Type 2 (SCA2)

Introduction

Spinocerebellar Ataxia Type 2 (Sca2) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Spinocerebellar Ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia, distinctive oculomotor abnormalities, and variable additional features including peripheral neuropathy and cognitive impairment. It is caused by a CAG trinucleotide repeat expansion in the ATXN2 gene and is one of the most common spinocerebellar ataxias worldwide[@spinocerebellar2008].

Overview

Spinocerebellar Ataxia type 2 is a member of the polyglutamine disease family, sharing pathogenic mechanisms with SCA1, Huntington's Disease, and other trinucleotide repeat disorders. SCA2 was first described as a distinct clinical entity in the late 1980s, and the causative gene (ATXN2) was identified in 1996[@moderate1996].

The prevalence of SCA2 varies geographically, with higher frequencies in populations including those of Cuban, Indian, and Japanese descent. In Cuba, SCA2 accounts for up to 30% of all autosomal dominant cerebellar ataxias, representing the most common SCA in that population[@molecular2006]. The disease typically manifests in the second to fourth decade of life, though juvenile-onset cases occur with larger repeat expansions.

Neuropathologically, SCA2 is characterized by prominent degeneration of the cerebellar Purkinje cells, the inferior olivary nuclei, and the basal ganglia. The pattern of neurodegeneration correlates with the characteristic clinical presentation of ataxia, slow saccadic eye movements, and the occasional presence of parkinsonian features[@neuropathological2015].

Genetics

Inheritance Pattern

SCA2 follows an autosomal dominant inheritance pattern with high penetrance[@spinocerebellar2008][@moderate1996]:

• CAG repeat expansion: Pathogenic mutation is an expanded CAG trinucleotide repeat in the ATXN2 gene on chromosome 12q24.1
• Normal alleles: 13-31 CAG repeats
• Intermediate alleles: 32-33 repeats (may be unstable)
• Full mutation alleles: 34-200+ repeats (disease-causing)
• Anticipation: Larger repeats are associated with earlier onset, particularly through paternal transmission

The ATXN2 Gene

The ATXN2 gene encodes the protein ataxin-2, which plays important roles in cellular RNA metabolism[@moderate1996][@ataxin2020]:

• Normal function: Ataxin-2 is involved in RNA splicing, translation regulation, and stress granule formation
• Pathogenic mechanism: The expanded polyglutamine tract causes toxic gain-of-function, leading to RNA metabolism dysregulation and cellular stress
• Expression pattern: Widely expressed in the central nervous system, with high levels in Purkinje cells and cerebellar nuclei
• Normal function: Ataxin-2 interacts with multiple RNA-binding proteins and is involved in translational control

Genotype-Phenotype Correlations

The number of CAG repeats influences the clinical presentation[@molecular2006][@spinocerebellar2019]:

| Repeat Count | Age of Onset | Phenotype |
|--------------|--------------|-----------|
| 34-45 | 30-50 years | Adult-onset, slow progression |
| 46-75 | 15-30 years | Juvenile onset, moderate progression |
| 76+ | Childhood | Early onset, rapid progression, severe |

Patients with very large expansions (>100 repeats) may present with a childhood-onset form characterized by more severe cognitive impairment and rapid disease progression.

Pathophysiology

Molecular Mechanisms

The pathogenesis of SCA2 involves multiple interconnected mechanisms[@ataxin2020][@molecular2010]:

Polyglutamine toxicity: Mutant ataxin-2 forms intracellular aggregates that disrupt normal neuronal function

RNA metabolism dysregulation: Ataxin-2 is a key component of stress granules and RNA processing complexes; mutant forms disrupt these structures

Translational control disruption: Impaired regulation of mRNA translation in affected [neurons](/entities/neurons)

Mitochondrial dysfunction: Energy metabolism deficits in degenerating [neurons](/entities/neurons)

Synaptic dysfunction: Impaired neurotransmission at cerebellar synapses

Glial involvement: Emerging evidence suggests non-neuronal cells may contribute to disease progression

Neuropathology

Post-mortem studies of SCA2 patients reveal characteristic findings[@neuropathological2015][@autosomal2013]:

• Cerebellar degeneration: Severe loss of Purkinje cells throughout the cerebellar [cortex](/brain-regions/cortex)
• Inferior olivary nucleus degeneration: Prominent neuronal loss in the inferior olive
• Brainstem pathology: Degeneration of the pons and midbrain nuclei
• Basal ganglia involvement: Variable involvement of the striatum and subthalamic nucleus
• Peripheral neuropathy: Loss of anterior horn cells and dorsal root ganglia neurons
• Cerebral [cortex](/brain-regions/cortex): Variable involvement, with some patients showing cortical atrophy

Clinical Features

Core Neurological Manifestations

The clinical presentation of SCA2 is dominated by cerebellar dysfunction[@spinocerebellar2008][@spinocerebellar2019]:

• Progressive ataxia: Limb and gait ataxia, typically beginning with gait instability and progressing to involve all limbs
• Slow saccadic eye movements: Characteristic oculomotor finding that distinguishes SCA2 from many other SCAs
• Dysarthria: Cerebellar-type scanning speech
• Dysphagia: Progressive swallowing difficulty in moderate to advanced disease
• Nystagmus: Horizontal and vertical nystagmus, particularly on lateral gaze

Additional Neurological Features

SCA2 may present with additional neurological manifestations[@spinocerebellar2019][@hereditary1998]:

• Peripheral neuropathy: Reduced or absent reflexes, particularly in the lower extremities
• Cognitive impairment: Mild to moderate cognitive deficits, particularly in executive function and verbal memory
• Parkinsonian features: Resting tremor and bradykinesia may occur in some patients
• Myoclonus: Rare, but reported in some families
• Chorea: May occur in patients with very large repeat expansions

Juvenile-Onset SCA2

Patients with early onset (childhood) due to large repeat expansions present with[@early2011]:

• More rapid disease progression
• Prominent cognitive impairment
• Earlier loss of ambulation
• Greater severity of dysarthria and dysphagia

Diagnosis

Clinical Diagnosis

SCA2 is suspected in patients with progressive cerebellar ataxia and characteristic features[@spinocerebellar2008]:

• Progressive cerebellar ataxia
• Slow saccadic eye movements (highly characteristic)
• Family history consistent with autosomal dominant inheritance
• Possible peripheral neuropathy or mild cognitive impairment

Genetic Testing

Definitive diagnosis requires molecular genetic testing[@moderate1996]:

• CAG repeat analysis: PCR-based detection of expanded CAG repeats in the ATXN2 gene
• Confirmatory testing: Repeat sizing for prognostic information
• Differential diagnosis testing: Panel testing for other SCAs may be appropriate
• Prenatal testing: Available for families with known mutations

Differential Diagnosis

SCA2 must be distinguished from other spinocerebellar ataxias and mimics[@autosomal2010]:

• SCA1: Faster progression, no slow saccades, prominent dysarthria
• SCA3/MJD: May have parkinsonism, muscle atrophy, ophthalmoplegia
• SCA6: Pure cerebellar ataxia, later onset, generally benign course
• Friedreich's Ataxia: Autosomal recessive, earlier onset, cardiomyopathy
• Multiple System Atrophy (MSA-C): Sporadic, adult-onset cerebellar ataxia

Diagnostic Workup

• MRI brain: Shows cerebellar atrophy, particularly of the vermis and hemispheres; brainstem atrophy may be present
• Neurological examination: Documents ataxia severity, eye movement abnormalities, and associated findings
• Oculographic testing: Can quantify slow saccades characteristic of SCA2
• Nerve conduction studies: May show peripheral neuropathy in some patients
• Cognitive testing: Documents any cognitive impairment

Treatment

Disease-Modifying Therapies

Currently, no FDA-approved disease-modifying therapy exists for SCA2, but multiple therapeutic approaches are under investigation[@spinocerebellar2018]:

• RNA-targeted therapies: Antisense oligonucleotides (ASOs) and RNAi approaches to reduce mutant ATXN2 expression
• Small molecule modulators: Compounds targeting ataxin-2 aggregation or its protein interactions
• Gene therapy: Viral vector-mediated gene silencing approaches
• Repurposing efforts: Screen of approved drugs for potential disease-modifying effects

Symptomatic Management

Comprehensive multidisciplinary care is essential for SCA2 patients[@spinocerebellar2019][@hereditary1998]:

Rehabilitation

• Physical therapy: Balance training, gait exercises, and fall prevention
• Occupational therapy: Adaptive devices and home safety modifications
• Speech therapy: Communication strategies and dysphagia management

Pharmacological

• Movement disorder medications: For associated parkinsonism (levodopa may provide benefit in some patients)
• Muscle relaxants: For spasticity if present
• Antidepressants: For depression and anxiety
• Anticholinergics: May help with excessive drooling

Supportive Care

• Assistive devices: Canes, walkers, and wheelchairs as disease progresses
• Home modifications: Grab bars, ramps, and barrier-free living spaces
• Nutrition: Dietary modifications and gastrostomy tube placement for severe dysphagia

Experimental Approaches

Current research directions include[@spinocerebellar2018]:

• ASO therapy: Multiple programs are developing ASOs to silence ATXN2
• Protein interaction modulators: Targeting ataxin-2's interactions with RNA-binding proteins
• Stress granule modulators: Compounds affecting stress granule dynamics
• Neuroprotective strategies: Supporting neuronal survival and function

Clinical Trials

Active and recent research in SCA2[@clinicaltrialsgov]:

| Phase | Treatment | Target | Status |
|-------|-----------|--------|--------|
| Preclinical | ASO therapy | ATXN2 | Research |
| Preclinical | Gene therapy | ATXN2 silencing | Research |
| Preclinical | Small molecules | Ataxin-2 modulators | Research |

Prognosis

SCA2 is a progressive neurodegenerative disorder with variable course[@spinocerebellar2019][@hereditary1998]:

• Median survival: 15-25 years after symptom onset
• Disease progression: Typically slower than SCA1, with slower saccades and less severe dysarthria
• Loss of ambulation: Usually occurs 10-20 years after onset
• Cause of death: Aspiration pneumonia, respiratory complications, or falls
• Prognostic factors: Repeat size correlates with age of onset but not strongly with rate of progression

Research Directions

Current research focuses on[@spinocerebellar2018][@spinocerebellar2018a]:

Understanding ataxin-2 function: Normal biology and pathogenic mechanisms

Therapeutic development: ASOs, gene therapy, and small molecule approaches

Biomarkers:markers for disease progression and treatment response

Clinical endpoints: Natural history studies to support clinical trials

RNA metabolism: Understanding ataxin-2's role in RNA processing

Stress granules: Role of these cytoplasmic organelles in SCA2 pathogenesis

• [Spinocerebellar Ataxia Type 1 (SCA1)](/diseases/spinocerebellar-ataxia-type-1) - Another common SCA with faster progression
• [Machado-Joseph Disease (SCA3)](/diseases/machado-joseph-disease) - Most common SCA worldwide
• [Spinocerebellar Ataxia Type 6](/diseases/spinocerebellar-ataxia-type-6) - Pure cerebellar ataxia
• [Parkinson's disease](/diseases/parkinsons-disease) - May share some clinical features with SCA2
• [Amyotrophic Lateral Sclerosis (ALS)](/diseases/als) - ATXN2 expansions are a risk factor for ALS
• [cerebellum](/brain-regions/cerebellum) - Primary brain region affected in SCA2
• [Cerebellar Ataxia](/diseases/cerebellar-ataxia) - Clinical syndrome
• [Polyglutamine Diseases - Overview of trinucleotide repeat disorders](/companies/overview)
• [Slow Saccades - Characteristic eye movement abnormality in SCA2](/genes/ar)

External Links

• [National Ataxia Foundation](https://ataxia.org/)
• [Spinocerebellar Ataxia Research Foundation](https://www.scARF.org/)
• [Genetic and Rare Diseases Information Center - SCA2](https://rarediseases.info.nih.gov /diseases/5192/sca2)
• [ClinicalTrials.gov - SCA2](https://clinicaltrials.gov/ct2/results?cond=SCA2)

Background

The study of Spinocerebellar Ataxia Type 2 (Sca2) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

Recent Research (2024-2026)

Recent advances in Spinocerebellar Ataxia Type 2 (SCA2) have focused on understanding disease mechanisms, identifying biomarkers, and developing novel therapeutic approaches. Key developments include:

• Genetic studies: Identification of new genetic risk factors and mechanistic insights
• Biomarker research: Development of diagnostic and prognostic biomarkers
• Therapeutic approaches: Investigation of novel treatment strategies
• Clinical trials: Ongoing Phase I-III trials for new therapies

Allen Brain Atlas Resources

• [Allen Brain Atlas - Gene Expression](https://human.brain-map.org/) - Search for gene expression data across brain regions
• [Allen Brain Atlas - Cell Types](https://celltypes.brain-map.org/) - Explore neuronal cell type taxonomy
• [Allen Brain Atlas - Aging, Dementia & TBI](https://aging.brain-map.org/) - Data on aging and traumatic brain injury
• [BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/) - Developmental gene expression data

Future Directions

Gene Therapy Advances

Emerging gene therapy approaches offer promise for SCA2 treatment:

• AAV vectors: Adeno-associated virus delivery of shRNA or ASO sequences
• CRISPR-Cas13: RNA-targeting CRISPR systems for allele-specific silencing
• Prime editing: Potential for direct correction of CAG repeat expansion

Stem Cell Approaches

Induced pluripotent stem cell (iPSC) technology enables disease modeling and therapy development:

• Patient-derived iPSCs: Provide human neuronal models for drug testing
• Cell replacement: Cerebellar neuron transplantation approaches
• Gene correction: CRISPR-based correction of repeat expansions in iPSCs

International Collaboration

Global efforts accelerate SCA2 research:

• European Spinocerebellar Ataxia Registry (ESCAR): Multinational patient registry
• Clinical Research Consortium for SCA (CRC-SCA): US-based natural history studies
• International Ataxia Research Consortium (IARC): Global research coordination

Neuroimaging Findings

MRI Characteristics

MRI findings in SCA2 reflect the characteristic neuropathology:

• Cerebellar atrophy: Predominant in the cerebellar vermis and hemispheres
• Brainstem atrophy: Pontine and inferior olivary involvement
• Fourth ventricle dilation: Secondary to cerebellar atrophy
• Middle cerebellar peduncle atrophy: Often evident in advanced disease
• Cortical atrophy: Variable, may be prominent in patients with cognitive impairment

Advanced Imaging Techniques

Advanced MRI techniques provide insights into microstructural changes:

• Diffusion tensor imaging (DTI): Reveals white matter tract damage beyond structural MRI
• Magnetic resonance spectroscopy (MRS): Shows metabolic changes in affected brain regions
• Resting-state fMRI: Identifies functional connectivity alterations in cerebellar networks

PET Findings

FDG-PET studies demonstrate characteristic hypometabolism:

• Cerebellar hypometabolism: Most consistent finding, correlates with ataxia severity
• Brainstem hypometabolism: Inferior olive and pons
• Cortical hypometabolism: Variable, may involve frontal and parietal regions
• Thalamic involvement: Some patients show thalamic hypometabolism

Comorbidities and Complications

Neurological Comorbidities

SCA2 patients may develop additional neurological conditions:

• Migraine: Higher prevalence than general population
• Epilepsy: Rare but reported in some families
• Depression and anxiety: Common psychological comorbidities
• Sleep disorders: Including REM sleep behavior disorder

Systemic Complications

Non-neurological complications affect quality of life:

• Aspiration pneumonia: Leading cause of mortality, due to dysphagia
• Malnutrition: Result of dysphagia and feeding difficulties
• Pressure ulcers: In immobile patients
• Deep vein thrombosis: In sedentary patients
• Urinary tract infections: Related to bladder dysfunction

Quality of Life

Functional Impact

SCA2 progressively affects daily functioning:

• Mobility: From intermittent falls to wheelchair dependency
• Self-care: Dressing, grooming become increasingly difficult
• Communication: Dysarthria progresses to near-anarthria
• Swallowing: Gradual progression to gastrostomy dependence

Psychosocial Impact

The disease affects psychological wellbeing and social participation:

• Social isolation: Due to mobility limitations and communication difficulties
• Employment: Early retirement common due to functional decline
• Financial burden: Medical costs, assistive devices, home modifications
• Caregiver burden: Family members experience significant stress

Supportive Interventions

Comprehensive support improves quality of life:

• Psychological counseling: Addresses depression, anxiety, adjustment
• Social work services: Assists with resource navigation
• Peer support: Connection with other SCA2 patients
• Palliative care: Symptom management and quality of life optimization

Cellular Mechanisms

RNA Granule Dysregulation

Ataxin-2 is a key component of stress granules, cytoplasmic organelles that form in response to cellular stress:

• Stress granule formation: Under stress, ATXN2 relocates to stress granules
• mRNA regulation: Stress granules temporarily store translationally stalled mRNAs
• Translation repression: Mutant ATXN2 disrupts normal stress granule dynamics
• Cytoplasmic RNA foci: Expanded repeats cause formation of toxic RNA foci

Protein Aggregation

The polyglutamine expansion leads to abnormal protein aggregation:

• Aggregate formation: Mutant ataxin-2 forms insoluble aggregates
• Sequestration: Aggregates can sequester normal proteins and RNA
• Proteostasis disruption: Cellular protein quality control systems are overwhelmed
• Autophagy impairment: Aggregate clearance mechanisms are compromised

Mitochondrial Dysfunction

Energy metabolism is impaired in SCA2:

• Complex I deficiency: Respiratory chain abnormalities detected
• ATP production: Reduced cellular energy reserves
• Oxidative stress: Increased reactive oxygen species production
• Calcium dysregulation: Mitochondrial calcium handling is impaired

Synaptic Dysfunction

Cerebellar synaptic transmission is compromised:

• Purkinje cell synapses: Climbing fiber and parallel fiber inputs affected
• Neurotransmitter release: Impaired glutamate and GABA signaling
• Synaptic plasticity: Long-term depression and potentiation disrupted
• Dendritic pathology: Purkinje cell dendritic arborization reduced

Neuroimmune Interactions

Glial Cell Involvement

Non-neuronal cells contribute to disease progression:

• Microglial activation: Chronic neuroinflammation present in patient brains
• Astrocytic dysfunction: Altered glutamate metabolism
• Oligodendrocyte involvement: White matter pathology evident
• Peripheral immune cells: Monocyte infiltration observed

Inflammatory Mediators

Elevated inflammatory markers in SCA2:

• Cytokines: TNF-alpha, IL-1beta, IL-6 elevated in CSF
• Chemokines: CCL2 and CXCL10 increased
• Complement system: Activation markers present
• MicroRNA dysregulation: Inflammatory miRNAs altered

Therapeutic Targets

RNA-Targeting Strategies

Multiple approaches aim to reduce mutant ATXN2 expression:

• Antisense oligonucleotides (ASOs): Single-stranded DNA that hybridize to target RNA
• RNAi: siRNA and shRNA-mediated gene silencing
• Small molecule splicing modulators: Alter ATXN2 splicing
• Ribonuclease P: Target repeat-containing RNA for degradation

Protein-Targeting Approaches

Alternative strategies target the mutant protein:

• Aggregation inhibitors: Small molecules that prevent aggregate formation
• Autophagy enhancers: Promote clearance of mutant protein
• Protein stabilizers: Compounds that stabilize normal protein conformation
• Heat shock protein modulators: Enhance protein folding capacity

Neuroprotective Strategies

Supporting neuronal survival:

• Antioxidants: Combat oxidative stress
• Mitochondrial protectants: Support energy metabolism
• Anti-inflammatory agents: Reduce neuroinflammation
• Neurotrophic factors: BDNF and related compounds

Conclusion

Spinocerebellar Ataxia Type 2 represents a complex neurodegenerative disorder involving multiple pathogenic mechanisms. The identification of ATXN2 as the causative gene has enabled detailed molecular characterization and therapeutic development efforts. While no disease-modifying therapy currently exists, the pipeline of RNA-targeting and neuroprotective approaches offers hope for patients. Ongoing natural history studies and biomarker research will be critical for successful clinical trials. The development of effective treatments for SCA2 will not only benefit patients with this specific disorder but will also advance understanding of related polyglutamine diseases and fundamental mechanisms of neurodegeneration.

Recent Advances (2024-2025)

Recent research has yielded important insights into SCA2 pathogenesis and treatment:

• Ataxin-2 phosphorylation: New studies identify phosphorylation sites that modify toxicity
• TDP-43 interactions: Links between ATXN2 and TDP-43 pathology in ALS
• Blood biomarkers: NfL and pNfH show promise for disease progression tracking
• ASO clinical trials: First-in-human studies initiated for RNA-targeted therapy

Pathway Diagram

References

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