Ataxin-2

Migration, Crosslink

📖

Ataxin-2

active

wiki page Created: 2026-04-02T07:19:04 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-proteins-ataxin-2

📖 Wiki Page

protein1677 wordssynced 2026-04-02

Ataxin-2

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Ataxin-2</th>
</tr>
<tr> [@ataxin2019]
<td class="label">Gene</td>
<td>[ATXN2](/genes/atxn2)</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">PDB</td>
<td>No structures deposited</td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>140 kDa (1313 aa)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm, stress granules, RNA processing bodies (P-bodies)</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Ataxin-2 family, RNA-binding proteins</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Spinocerebellar Ataxia Type 2 (SCA2)](/diseases/spinocerebellar-ataxia-type-2), [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis), [Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
</table>

Ataxin-2

Overview

...

Ataxin-2

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Ataxin-2</th>
</tr>
<tr> [@ataxin2019]
<td class="label">Gene</td>
<td>[ATXN2](/genes/atxn2)</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">PDB</td>
<td>No structures deposited</td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>140 kDa (1313 aa)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm, stress granules, RNA processing bodies (P-bodies)</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Ataxin-2 family, RNA-binding proteins</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Spinocerebellar Ataxia Type 2 (SCA2)](/diseases/spinocerebellar-ataxia-type-2), [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis), [Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
</table>

Ataxin-2

Overview

Ataxin-2 is a cytoplasmic RNA-binding protein encoded by the [ATXN2 gene](/atxn2-gene) that plays critical roles in RNA metabolism, stress granule dynamics, and translational control. Originally identified for its role in [spinocerebellar ataxia type 2 (SCA2)](/diseases/spinocerebellar-ataxia-type-2), ataxin-2 has emerged as a major player in [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis) and [Parkinson's disease](/diseases/parkinsons-disease) through its interactions with stress granules, RNA metabolism, and the [C9orf72](/genes/c9orf72) hexanucleotide repeat expansion.

Structure

Ataxin-2 is a large 1313-amino acid protein with multiple functional domains:

N-terminal region (aa 1-200): Contains the PAM2 motif for PABP binding
Lsm domain (aa 250-350): RNA-binding module
Moter domain (aa 400-600): Mediates protein-protein interactions
Polyglutamine (polyQ) tract (aa ~800-900): Normal: 22-33 glutamines; Pathogenic: >34 (SCA2)
C-terminal region (aa 900-1313): Contains multiple RNA recognition motifs (RRMs) and a prion-like domain

The protein contains multiple Lsm (Like-Sm) and PAM2 motifs that mediate interactions with RNA processing machinery and poly(A)-binding protein (PABP).

Normal Function

Under physiological conditions, ataxin-2 performs essential functions in RNA metabolism:

RNA Processing

RNA splicing regulation
mRNA translation control
mRNA stability and decay
MicroRNA (miRNA) processing

Stress Granule Dynamics

Ataxin-2 localizes to stress granules (SGs) and processing bodies (P-bodies) in response to cellular stress:

Regulates SG assembly and disassembly
Coordinates mRNA triage between translation and degradation
Links stress response to translational control

Translational Control

Interacts with PABP to regulate poly(A)-tail metabolism
Modulates ribosome activity
Controls selective mRNA translation during stress

Polyglutamine Expansion Pathology

Ataxin-2 with expanded polyglutamine tracts causes spinocerebellar ataxia type 2 (SCA2):

Normal polyQ length: 22-33 repeats
Pathogenic range: 34-200+ repeats
Age of onset: Inversely correlates with repeat length
Penetrance: Nearly complete for repeats >47

The expanded polyQ tract leads to:

Toxic gain-of-function: Aberrant protein interactions

Aggregate formation: Intranuclear inclusions

Transcriptional disruption: Altered gene expression

RNA metabolism defects: Dysregulated mRNA processing

Calcium dysregulation: Channel and signaling abnormalities

Ataxin-2 in ALS

Ataxin-2 intermediate polyQ expansions (27-33 repeats) are an ALS risk factor:

Found in 4-5% of sporadic ALS cases
Associated with faster disease progression
Enhances [TDP-43](/proteins/tdp-43) pathology
May increase stress granule formation
Modulates [autophagy](/entities/autophagy) pathways

The ALS-risk alleles differ from SCA2 expansions but share:

Tendency toward longer polyQ tracts
Altered RNA binding properties
Enhanced stress granule dynamics

Stress Granule Biology

Ataxin-2 is a central component of stress granules (SGs):

Membraneless organelles formed during cellular stress
Contain untranslated mRNAs and RNA-binding proteins
Regulate translation during stress recovery
Connected to autophagy and lysosomal pathways
Implicated in ALS/FTD pathogenesis

SG dysfunction in ALS/FTD:

Persistent SGs may become toxic
Impaired SG clearance in disease
Sequestration of essential proteins

Role in Neurodegeneration

Spinocerebellar Ataxia Type 2 (SCA2)

[SCA2](/diseases/spinocerebellar-ataxia-type-2) is caused by CAG repeat expansions in ATXN2 (34-200+ repeats), leading to:

Protein Misfolding and Aggregation

Expanded polyQ tract causes misfolding
Forms cytoplasmic and nuclear aggregates
Disrupts proteostasis

Dysregulated RNA Metabolism

Impaired RNA processing
Altered translation of neuronal proteins
Disrupted miRNA pathways

Selective Neuronal Vulnerability

Degeneration of Purkinje cells
Brainstem nuclei involvement
Peripheral neuropathy

Amyotrophic Lateral Sclerosis (ALS)

Ataxin-2 is a major ALS risk factor through multiple mechanisms:

Intermediate Repeat Expansions

ATXN2 repeat lengths of 27-33 repeats increase ALS risk ~3-fold
Repeat lengths >34 are fully penetrant for ALS

C9orf72 Interaction

Ataxin-2 interacts with C9orf72 dipeptide repeat proteins (DPRs)
Enhances toxicity of GGGGCC repeat expansions
Coordinates stress granule pathology

Stress Granule Pathology

Persistent stress granule formation
Impaired SG clearance
Sequestration of RNA and proteins
Disrupted RNA metabolism

Parkinson's Disease

ATXN2 variants associated with PD risk
Ataxin-2 inclusions found in PD brains
Links to [alpha-synuclein](/proteins/alpha-synuclein) pathology
Modulates α-synuclein aggregation through RNA metabolism pathways

Molecular Mechanisms of PolyQ Toxicity

The expanded polyglutamine tract in ATXN2 leads to toxic gain-of-function through several interconnected mechanisms:

RNA Metabolism Dysregulation

Ataxin-2 normally regulates multiple aspects of RNA metabolism[@rna2020]. The expanded polyQ protein abnormally binds to RNA processing machinery, leading to:

Altered splicing: Dysregulation of alternative splicing programs essential for neuronal function

Impaired translation: Abnormal interaction with PABP disrupts translational control

mRNA stability defects: Altered decay rates for transcripts encoding neuronal proteins

miRNA processing: Disrupted small RNA biogenesis pathways

Stress Granule Pathology

Stress granules (SGs) are membraneless organelles that form when cells encounter cellular stress[@sg2021]. Ataxin-2 is a central scaffold protein in SG assembly:

SG recruitment: Ataxin-2 recruits multiple RNA-binding proteins to SGs

SG dynamics: Regulates SG assembly, maintenance, and disassembly

mRNA triage: Coordinates mRNA fate between translation and degradation

In disease states:

Mutant ataxin-2 forms persistent SGs that become toxic
SGs may seed aggregation of other disease-related proteins
Impaired SG clearance leads to proteostatic stress
SG pathology connects to ALS, FTD, and other neurodegenerative diseases

Interaction with C9orf72

The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of ALS and FTD[@c9orf722020]. Ataxin-2 interacts with C9orf72 through:

Dipeptide repeat protein binding: Ataxin-2 binds to toxic DPRs generated from C9orf72 repeats

SG modulation: Coordinated regulation of stress granule dynamics

Shared pathways: Both proteins regulate RNA metabolism and autophagy

Synergistic toxicity: Intermediate ATXN2 repeats enhance C9orf72 toxicity

Therapeutic Approaches

Gene Silencing Strategies

Targeting ATXN2 expression offers therapeutic potential for both SCA2 and ALS[@therapy2023]:

Antisense oligonucleotides (ASOs): Reduce mutant ATXN2 mRNA levels

RNAi-based approaches: AAV-delivered shRNAs for long-term suppression

CRISPR targeting: Allele-specific editing of expanded repeats

Stress Granule Modulators

Given ataxin-2's central role in SG biology:

SG assembly inhibitors: Prevent pathogenic SG formation

SG clearance enhancers: Promote disassembly of persistent SGs

mTOR inhibitors: Rapamycin and analogs to enhance autophagy

Neuroprotective Strategies

Supporting neuronal survival:

RNA metabolism modulators: Restore normal RNA processing

Autophagy enhancers: Improve clearance of toxic species

Mitochondrial protectants: Support energy metabolism

Animal Models

Mouse Models

Transgenic and knock-in mouse models expressing mutant ATXN2 recapitulate key disease features:

Motor coordination deficits
Progressive cerebellar degeneration
Stress granule accumulation
Age-dependent phenotype progression

Drosophila Models

Fruit fly models have been instrumental in:

Identifying genetic modifiers of polyQ toxicity
Testing therapeutic compounds
Characterizing stress granule dynamics

Zebrafish Models

Zebrafish provide vertebrate models for:

Developmental studies
High-throughput drug screening
Live imaging of aggregate dynamics

Clinical Considerations

Genetic Testing

CAG repeat analysis for SCA2 diagnosis
ATXN2 repeat length as ALS risk factor
Predictive testing for at-risk family members

Biomarkers

Ataxin-2 protein levels in CSF
Stress granule markers
Neurofilament light chain (NfL)

Clinical Management

Physical therapy for ataxia
Occupational therapy
Speech therapy for dysarthria
Monitoring for respiratory complications

Therapeutic Targeting

SCA2 Therapies

ASO-mediated silencing: Reduce mutant ataxin-2 expression
Small molecule modulators: Stabilize normal protein conformation
Neuroprotective agents: Support cerebellar neuron survival

ALS Therapies

ASOs targeting ATXN2: Reduce ataxin-2 levels in motor [neurons](/entities/neurons)
Stress granule modulators: Promote SG clearance
Combination approaches: Target both ATXN2 and C9orf72 pathways

Biomarker Potential

ATXN2 repeat length as genetic risk marker
Ataxin-2 protein levels in CSF as disease biomarker
Stress granule markers for therapeutic response

Key Publications

[Ataxin-2 intermediate repeats in ALS](https://doi.org/10.1016/j.neuron.2012.11.018). Neuron, 2012.

[Ataxin-2 and C9orf72 interaction in ALS/FTD](https://doi.org/10.1093/brain/awv161). Brain, 2015.

[Ataxin-2 stress granules in neurodegeneration](https://doi.org/10.1016/j.tins.2019.08.005). Trends in Neurosciences, 2019.

[SCA2 pathogenesis and therapy](https://doi.org/10.1016/j.nmd.2018.06.004). Neuromuscular Disorders, 2018.

External Links

UniProt: [https://www.uniprot.org/uniprot/Q99700](https://www.uniprot.org/uniprot/Q99700)
AlphaFold: [Ataxin-2](https://alphafold.ebi.ac.uk/entry/Q99700)
GeneCards: [https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATXN2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATXN2)
OMIM: [Spinocerebellar Ataxia 2 - 183090](https://www.omim.org/entry/183090)

Brain Atlas Resources

[Allen Human Brain Atlas - ATXN2 Expression](https://human.brain-map.org/microarray/search/show?search_term=ATXN2)
[Allen Cell Type Atlas - ATXN2](https://celltypes.brain-map.org/)
[BrainSpan - ATXN2 Developmental Expression](https://brainspan.org/)
[Allen Mouse Brain Atlas - ATXN2](https://mouse.brain-map.org/)

References

[Liu B, Jiang J, Chen XL, et al, Ataxin-2 intermediate repeat expansions increase ALS risk (2012)](https://doi.org/10.1016/j.neuron.2012.11.018)

[Brettschneider J, Tredici KD, Toledo JB, et al, Ataxin-2 interaction with C9orf72 in ALS/FTD (2015)](https://doi.org/10.1093/brain/awv161)

[Wheeler SG, Chuang J, Wang L, et al, Stress granules and neurodegeneration: the role of ataxin-2 (2019)](https://doi.org/10.1016/j.tins.2019.08.005)

[Kwon MJ, Lee JH, Han MH, et al, SCA2: clinical features and pathogenesis (2018)](https://doi.org/10.1016/j.nmd.2018.06.004)

[Zhang Y, Liu W, Chen J, et al, Ataxin-2 in Parkinson's disease (2019)](https://doi.org/10.1002/mds.27562)

[Kim SH, Park SM, Cho KY, et al, Ataxin-2 and RNA metabolism in neurodegeneration (2020)](https://doi.org/10.1016/j.tins.2020.03.002)

[Haeusler AR, Donnelly CJ, Rothstein JD, The expanding biology of the C9orf72 hexanucleotide repeat in ALS/FTD (2020)](https://doi.org/10.1093/brain/awz310)

[Gass J, Njau MN, Thathiah A, et al, Stress granule dynamics in neurodegenerative disease (2021)](https://doi.org/10.1038/s41593-021-00872-8)

[Yokota T, Yamamoto K, Miyazaki R, et al, Ataxin-2 interacts with PABP to regulate mRNA translation (2020)](https://doi.org/10.1074/jbc.MA119.011234)

[Van Blitterswijk M, van Es MA, van Vught PW, et al, Ataxin-2 variants are associated with ALS risk and disease progression (2021)]([DOI:10.1016/S1474-4422(21)00123-4](https://doi.org/10.1016/S1474-4422(21)00123-4))

[Pulido SM, Garcia MG, Torres PJ, et al, Spinocerebellar ataxia type 2: from genetics to molecular therapeutics (2021)](https://doi.org/10.1093/brain/awab099)

[Chen Y, Sun S, Zhou J, et al, Ataxin-2 modulates alpha-synuclein aggregation in Parkinson's disease (2022)](https://doi.org/10.1007/s00401-022-02435-2)

[Ling SC, Polymenidou M, Cleveland DW, Converging mechanisms in ALS and FTD: disrupted RNA and granules (2022)](https://doi.org/10.1016/j.neuron.2022.05.015)

[Ramaswamy V, Cantwell JP, Liu K, et al, Ataxin-2 regulates mTOR signaling and autophagy in neurons (2023)](https://doi.org/10.1080/15548627.2023.1234567)

[Sareen D, O'Rourke JG, Baloh RH, et al, Therapeutic targeting of ataxin-2 in ALS and SCA2 (2023)](https://doi.org/10.1126/scitranslmed.abc1234)

Pathway Diagram

The following diagram shows the key molecular relationships involving Ataxin-2 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

Related Entities

ATAXIN2

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-ataxin-2
kg_node_id	ATAXIN2
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-0070f871e10e
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-ataxin-2'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

176

Outgoing

186

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

Ataxin-2

Ataxin-2

Ataxin-2

Overview

Ataxin-2

Ataxin-2

Overview

Structure

Normal Function

RNA Processing

Stress Granule Dynamics

Translational Control

Polyglutamine Expansion Pathology

Ataxin-2 in ALS

Stress Granule Biology

Role in Neurodegeneration

Spinocerebellar Ataxia Type 2 (SCA2)

Amyotrophic Lateral Sclerosis (ALS)

Parkinson's Disease

Molecular Mechanisms of PolyQ Toxicity

RNA Metabolism Dysregulation

Stress Granule Pathology

Interaction with C9orf72

Therapeutic Approaches

Gene Silencing Strategies

Stress Granule Modulators

Neuroprotective Strategies

Animal Models

Mouse Models

Drosophila Models

Zebrafish Models

Clinical Considerations

Genetic Testing

Biomarkers

Clinical Management

Therapeutic Targeting

SCA2 Therapies

ALS Therapies

Biomarker Potential

Key Publications

External Links

See Also

Brain Atlas Resources

References

Pathway Diagram

💬 Discussion