ATXN1 — Ataxin 1

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ATXN1 — Ataxin 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ATXN1 — Ataxin 1</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>ATXN1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ataxin 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>6p22.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/6310" target="_blank">6310</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000124788" target="_blank">ENSG00000124788</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/601556" target="_blank">601556</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P54253" target="_blank">P54253</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Spinocerebellar Ataxia Type 1](/diseases/spinocerebellar-ataxias)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Purkinje cells, Cerebellum, Brainstem</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">CAG repeat expansion (>39 repeats pathogenic)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ataxia" style="color:#ef9a9a">Ataxia</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a></td>
</tr>
<tr>
<td cla

...

ATXN1 — Ataxin 1

Introduction

Atxn1 — Ataxin 1 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Ataxin 1 (ATXN1) is a nuclear protein encoded by the ATXN1 gene on chromosome 6p22.3. It is best known for causing Spinocerebellar Ataxia Type 1 (SCA1), a progressive autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia, motor dysfunction, and cognitive decline[^1]. The pathogenic mechanism involves a CAG trinucleotide repeat expansion in the coding region, resulting in an expanded polyglutamine (polyQ) tract in the mutant protein. The gene is catalogued as NCBI Gene ID [6310](https://www.ncbi.nlm.nih.gov/gene/6310) and OMIM [601556](https://omim.org/entry/601556).

Function

Normal Biological Role

Ataxin 1 is a transcriptional regulator that localizes primarily to the nucleus[^2]. Its normal functions include:

Transcriptional regulation: Ataxin 1 interacts with various transcription factors and co-repressors

Binds to RORα (retinoic acid-related orphan receptor alpha)
Interacts with histone deacetylases (HDACs)
Modulates Notch signaling

RNA processing: Associates with RNA splicing machinery

Cellular homeostasis: Involved in protein quality control and cellular stress responses

Neuronal function: Critical for Purkinje cell development and maintenance

Protein Structure

Ataxin 1 is an 815-amino acid protein with several key domains[^3]:

PolyQ tract: Normal range 6-35 glutamines; expanded to 36-130 in SCA1
AXH domain: Ataxin-1/hesx1 domain (residues 567-689); mediates protein-protein interactions
Nuclear localization signal (NLS): Arg/Lys-rich sequence for nuclear import
Phosphorylation sites: Ser776 phosphorylation is critical for toxicity

Brain Expression

Purkinje cells: Highest expression; primary site of pathology
Cerebellar cortex: Molecular and granular layers
Brainstem: Olivary nuclei, pons
Hippocampus: Lower expression
Cerebral cortex: Regional expression

Expression data is available from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=ATXN1).

Disease Associations

Spinocerebellar Ataxia Type 1 (SCA1)

SCA1 is an autosomal dominant neurodegenerative disorder and one of the most common polyglutamine diseases[^4].

Genetics

Inheritance: Autosomal dominant
Mutation: CAG trinucleotide repeat expansion in exon 8
Normal range: 6-35 repeats
Full penetrance: >41 repeats
Intermediate range: 36-39 repeats (reduced penetrance)

Clinical Features

Cerebellar symptoms:

Progressive gait ataxia (first symptom in ~70%)
Limb ataxia (dysmetria, dysdiadochokinesia)
Nystagmus (horizontal, vertical, or rotatory)
Dysarthria (scanning speech)
Dysphagia (swallowing difficulties)

Extrapyramidal features:

Parkinsonian features (bradykinesia, rigidity)
Dystonia
Chorea (less common)

Brainstem involvement:

Oculomotor abnormalities
Vertigo
Respiratory dysfunction (late)

Cognitive and psychiatric:

Executive dysfunction
Memory impairment
Depression, anxiety
Psychosis (rare)

Peripheral nervous system:

Peripheral neuropathy (less prominent than in other SCAs)
Reduced reflexes

Disease Progression

Age of onset: Typically 30-40 years (can be 4-70 years)
Disease duration: 10-30 years from onset to death
Rate of progression correlates with repeat length

Other Disease Associations

Multiple system atrophy (MSA): Some studies show ATXN1 repeat expansions in rare cases
SCA1-like phenotypes: ATXN1 variants may modify other ataxias

Pathogenesis

The Polyglutamine Toxicity Mechanism

The expanded polyQ tract in ataxin-1 leads to neurodegeneration through multiple interconnected mechanisms[^5]:

1. Protein Misfolding and Aggregation

Expanded polyQ promotes abnormal protein folding
Forms insoluble cytoplasmic and nuclear aggregates
Sequesters essential cellular proteins
Impairs ubiquitin-proteasome system

2. Transcriptional Dysregulation

Alters interactions with transcriptional regulators
Disrupts RORα-mediated gene expression
Impairs histone acetylation/deacetylation balance
Affects neurotrophic factor expression (BDNF)

3. Nuclear Transport Dysfunction

Mutant ataxin-1 accumulates in the nucleus
Alters nuclear pore function
Impairs nuclear-cytoplasmic transport

4. Mitochondrial Dysfunction

Reduces mitochondrial biogenesis
Increases oxidative stress
Impairs calcium homeostasis
Promotes apoptosis

5. Loss of Normal Function

The mutant protein loses normal regulatory functions
Dominant-negative effects on wild-type ataxin-1
Haploinsufficiency contributions

Neuropathology

Cerebellar degeneration: Loss of Purkinje cells
Brainstem atrophy: Inferior olivary nuclei, cranial nerve nuclei
Spinal cord involvement: Spinocerebellar tracts
Hippocampal pathology: Less severe than cerebellum

Diagnosis

Genetic Testing

Gold standard: PCR-based CAG repeat sizing
Confirmatory: Southern blot for large repeats
Preimplantation testing: Available for family planning

Neuroimaging

MRI: Cerebellar and brainstem atrophy
MR spectroscopy: Reduced N-acetylaspartate in cerebellum
Diffusion tensor imaging: White matter abnormalities

Clinical Evaluation

Neurological examination: Standardized Ataxia Rating Scales (SARA, ICARS)
Neuropsychological testing: Cognitive assessment
Electrophysiology: EMG, nerve conduction studies

Treatment and Management

Current Approaches

No cure exists for SCA1. Management is symptomatic and supportive[^6]:

Physical therapy: Gait training, balance exercises

Occupational therapy: Adaptive devices, home modifications

Speech therapy: For dysarthria and dysphagia

Medications:

Amitriptyline or gabapentin for neuropathic pain
Clonazepam for myoclonus
Botulinum toxin for dystonia

Emerging Therapies

Gene Silencing Approaches

| Approach | Status | Mechanism |
|----------|--------|-----------|
| ASOs | Preclinical | Target ATXN1 mRNA for degradation |
| RNAi | Preclinical | siRNA-mediated knock-down |
| CRISPR | Preclinical | allele-specific editing |

Small Molecule Therapies

HDAC inhibitors: Vorinostat, sodium butyrate (reduce toxic aggregation)
Autophagy inducers: Rapamycin, trehalose (enhance protein clearance)
Neurotrophic factors: BDNF mimetics
Antioxidants: CoQ10, vitamin E

Symptomatic Targets

Riluzole: Modulates glutamate, some benefit in ataxias
Varenicline: Cholinergic agonist, showed promise in SCA3
Aminopyridines: For downbeat nystagmus

Genotype-Phenotype Correlations

| Repeat Length | Age of Onset | Progression | Phenotype |
|--------------|--------------|-------------|------------|
| 36-39 | ~40-50 years | Slow | Mild |
| 40-50 | ~30-40 years | Moderate | Classic SCA1 |
| 51-70 | ~20-30 years | Rapid | Early-onset severe |
| >70 | <20 years | Very rapid | Juvenile onset |

Key Publications

[Identification and characterization of the gene causing type 1 spinocerebellar ataxia](https://doi.org/10.1038/ng1193-221). Nat Genet, 1993. PMID: 8275086(https://pubmed.ncbi.nlm.nih.gov/8275086/)

[Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease](https://doi.org/10.1016/S0092-8674(00)81781-X). Cell, 1998. PMID: 9729215(https://pubmed.ncbi.nlm.nih.gov/9729215/)

[Mutant ataxin-1 with expanded polyglutamine causes Purkinje cell degeneration and neurobehavioral abnormalities](https://doi.org/10.1073/pnas.0409802102). PNAS, 2004. PMID: 15574502(https://pubmed.ncbi.nlm.nih.gov/15574502/)

[SCA1: disease mechanisms and therapeutic targets](https://doi.org/10.1016/j.tig.2020.07.011). Trends in Genetics, 2020.

[Transcriptional dysregulation and cerebellar degeneration in SCA1](https://doi.org/10.1093/brain/awab320). Brain, 2021.

[Therapeutic targeting of SCA1](https://doi.org/10.1038/s41582-021-00543-0). Nature Reviews Neurology, 2021.

[Polyglutamine diseases: emerging therapeutic strategies](https://doi.org/10.1038/s41582-022-00641-w). Nature Reviews Neurology, 2022.

[Ataxin-1 interacts with RORα in cerebellar Purkinje cells](https://doi.org/10.1016/j.neuroscience.2019.07.012). Neuroscience, 2019.

External Links

NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/6310](https://www.ncbi.nlm.nih.gov/gene/6310)
Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000124788](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000124788)
OMIM: [https://omim.org/entry/601556](https://omim.org/entry/601556)
UniProt: [https://www.uniprot.org/uniprot/P54253](https://www.uniprot.org/uniprot/P54253)
Allen Human Brain Atlas: [ATXN1 expression](https://human.brain-map.org/microarray/search/show?search_term=ATXN1)
Spinocerebellar Ataxia Type 1 Foundation: [https://ataxin1.org](https://ataxin1.org)
spinocerebellar-ataxias
spinocerebellar-ataxias
polyglutamine-diseases
[neurons](/cell-types/neurons)
[Genes Index
[Proteins Index](/proteins) [--

Background

The study of Atxn1 — Ataxin 1 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.

Brain Atlas Resources

[Allen Human Brain Brain Atlas - ATXN1 Expression](https://human.brain-map.org/microarray/search/show?search_term=ATXN1)
[Allen Cell Type Atlas](https://celltypes.brain-map.org/)
[BrainSpan Transcriptome Atlas](https://brainspan.org/)
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/)

Pathway Diagram

Mermaid diagram (expand to render)

Disease Mechanism Summary

| GBA Variant | Enzyme Activity | PD Risk | Clinical Features |
|-------------|-----------------|---------|-------------------|
| N370S | 30-40% | 2-3x increased | Typical PD |
| L444P | <10% | 5x increased | Earlier onset |
| Recombinant | Variable | Variable | Severe |

References

[Soles A et al, Neural basis for mutant ATAXIN-1 induced respiratory dysfunction in mouse models of spinocerebellar ataxia type 1 (2026)](https://pubmed.ncbi.nlm.nih.gov/41850341/)

[Selimovic A et al, Mutant ATXN1 impacts human and mouse microglia and contributes to cognitive, mood, and motor deficits in SCA1 mice (2026)](https://pubmed.ncbi.nlm.nih.gov/41727128/)

[Kerkhof LMC et al, Impedance-based phenotypic profiling of metabotropic glutamate receptor ligand responses in SCA1 human iPSC-derived neuronal cultures (2026)](https://pubmed.ncbi.nlm.nih.gov/41620186/)

[Plotnikova E et al, Translational Relevance of SCA1 Models for the Development of Therapies for Spinocerebellar Ataxia Type 1 (2025)](https://pubmed.ncbi.nlm.nih.gov/41463080/)

[Singh S et al, Valosin-Containing Protein as a therapeutic target in CAG repeat-driven Spinocerebellar ataxias: Integrative transcriptomic and computational insights (2026)](https://pubmed.ncbi.nlm.nih.gov/41435767/)

[Woo DH et al, Oral KDS2010, a Monoamine Oxidase-B (MAO-B) Inhibitor), Slows the Deterioration of Motor Coordination in Genetic SCA1 Models by Inhibiting Astrocytic MAO-B-Mediated Inflammation (2025)](https://pubmed.ncbi.nlm.nih.gov/41427729/)

[Banez-Coronel M et al, Repeat-associated non-AUG translation as a common mechanism for the polyGln ataxias (2026)](https://pubmed.ncbi.nlm.nih.gov/41422503/)

[Goel P et al, Striatal pathology in Spinocerebellar Ataxia Type 1 mice: A comparative study with Huntington's disease (2025)](https://pubmed.ncbi.nlm.nih.gov/41415451/)

[Zhang JH et al, TMEM206 gene knockout improves balance performance in SCA1 transgenic mice (2025)](https://pubmed.ncbi.nlm.nih.gov/41377710/)

[Lee H et al, Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease (2025)](https://pubmed.ncbi.nlm.nih.gov/41279815/)

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