Ataxin-2 Protein
Overview
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Ataxin-2 Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>ATXN2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ataxin-2</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>ATXN2 (12q24.12)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>RNA-binding protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q99700" target="_blank">Q99700</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">View in Atlas</a></td>
</tr>
</table>
Ataxin-2 is an RNA-binding protein that plays crucial roles in RNA metabolism, translation regulation, and stress granule formation. The protein is encoded by the ATXN2 gene and contains a polyglutamine (polyQ) tract near its N-terminus. Expansion of this polyQ repeat beyond 34 glutamines causes spinocerebellar ataxia type 2 (SCA2), a progressive neurodegenerative disorder. Intermediate-length expansions (27-33 repeats) are a risk factor for amyotrophic lateral sclerosis (ALS) and Parkinson's disease.
Structure and Molecular Function
Ataxin-2 is a 140 kDa cytoplasmic protein containing several functional domains:
...Ataxin-2 Protein
Overview
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Ataxin-2 Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>ATXN2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ataxin-2</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>ATXN2 (12q24.12)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>RNA-binding protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q99700" target="_blank">Q99700</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">View in Atlas</a></td>
</tr>
</table>
Ataxin-2 is an RNA-binding protein that plays crucial roles in RNA metabolism, translation regulation, and stress granule formation. The protein is encoded by the ATXN2 gene and contains a polyglutamine (polyQ) tract near its N-terminus. Expansion of this polyQ repeat beyond 34 glutamines causes spinocerebellar ataxia type 2 (SCA2), a progressive neurodegenerative disorder. Intermediate-length expansions (27-33 repeats) are a risk factor for amyotrophic lateral sclerosis (ALS) and Parkinson's disease.
Structure and Molecular Function
Ataxin-2 is a 140 kDa cytoplasmic protein containing several functional domains:
- PolyQ tract: Variable length (normally 22-23 repeats); pathogenic when expanded
- Lsm domain: Facilitates RNA binding and protein-protein interactions
- PAM2 motif: Binds to PABPC1 (poly(A)-binding protein), linking ataxin-2 to mRNA regulation
- Prion-like domain: Promotes aggregation and stress granule formation
The protein functions primarily in:
Ataxin-2 regulates mRNA stability, translation, and localization. It associates with polyribosomes and modulates global protein synthesis, particularly under cellular stress conditions.
Stress Granule Dynamics
Under stress (heat shock, oxidative stress, nutrient deprivation), ataxin-2 is a core component of [stress granules](/mechanisms/stress-granules) - cytoplasmic aggregates of stalled translation machinery and mRNA. The protein helps nucleate these structures through its prion-like domain.
Endocytosis and Membrane Trafficking
Ataxin-2 interacts with endocytic proteins and regulates receptor-mediated endocytosis, particularly of EGFR (epidermal growth factor receptor) and other signaling receptors.
Role in Neurodegeneration
Spinocerebellar Ataxia Type 2 (SCA2)
SCA2 is caused by CAG repeat expansions (≥34 repeats) in ATXN2. The expanded polyQ tract causes:
- Progressive [cerebellar](/anatomy/cerebellum) degeneration, particularly Purkinje cells
- Ataxia (impaired coordination and balance)
- Slow saccadic eye movements
- Peripheral neuropathy
- Cognitive decline
The disease typically manifests in the third to fourth decade of life with progressive motor dysfunction. Pathologically, mutant ataxin-2 forms nuclear and cytoplasmic aggregates in affected neurons.
Amyotrophic Lateral Sclerosis (ALS)
Intermediate ATXN2 polyQ expansions (27-33 repeats) confer ~3-fold increased risk for [ALS](/diseases/als). The mechanism involves:
- Enhanced TDP-43 aggregation and toxicity
- Impaired stress granule dynamics
- Dysregulated RNA metabolism in motor neurons
Crucially, reducing ataxin-2 levels is protective in ALS models. Antisense oligonucleotide (ASO) therapy targeting
ATXN2 has shown promise in preclinical studies and is being developed for clinical trials.
Parkinson's Disease
Intermediate ATXN2 repeats also increase Parkinson's disease risk by ~1.5-fold. The protein interacts with alpha-synuclein and may influence its aggregation and toxicity.
Therapeutic Strategies
Antisense oligonucleotides targeting ATXN2 mRNA have emerged as a leading therapeutic approach:
- Reduces ataxin-2 protein levels in CNS
- Extends survival in ALS mouse models (TDP-43 and C9orf72)
- Well-tolerated in preclinical studies
- Clinical trials planned for ALS patients with intermediate expansions
Small Molecule Modulators
Compounds that modulate ataxin-2 function or aggregation are under investigation:
- Stress granule formation inhibitors
- Protein degradation enhancers (PROTACs)
- RNA-binding modulators
Gene Therapy Approaches
CRISPR-based approaches to reduce expanded allele expression or correct CAG repeats are in early research stages.
- [TDP-43](/proteins/tdp-43) - ALS-associated protein whose toxicity is modulated by ataxin-2
- [PABPC1](/proteins/pabpc1) - Poly(A)-binding protein partner
- [Spinocerebellar Ataxia](/diseases/sca) - Disease category including SCA2
- [ALS](/diseases/als) - Disease where ataxin-2 is a risk factor and therapeutic target
- [Stress Granules](/mechanisms/stress-granules) - Cellular structures regulated by ataxin-2
- [Purkinje Cells](/cell-types/purkinje-cells) - Cerebellar neurons vulnerable in SCA2
References
Becker LA, et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017;544(7650):367-371.
Elden AC, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010;466(7310):1069-1075.
Nonhoff U, et al. Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules. Mol Biol Cell. 2007;18(4):1385-1396.
Scoles DR, et al. Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature. 2017;544(7650):362-366.External Links
- [UniProt: ATXN2](https://www.uniprot.org/uniprot/Q99700)
- [OMIM: Spinocerebellar Ataxia 2](https://www.omim.org/entry/183090)
- [GeneCards: ATXN2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATXN2)
- [PubMed: Ataxin-2 therapeutic strategies](https://pubmed.ncbi.nlm.nih.gov/?term=ataxin-2+therapy)