SCA3 — ATXN3 (Ataxin-3)

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SCA3 — ATXN3 (Ataxin-3)

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SCA3 — ATXN3 (Ataxin-3)

Overview

Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is the most common dominant ataxia worldwide. The disease is caused by a CAG trinucleotide repeat expansion in the ATXN3 gene, which encodes the protein ataxin-3. This autosomal dominant disorder leads to progressive neurodegeneration primarily affecting the cerebellum, brainstem, and spinal cord, resulting in ataxia, dysarthria, ophthalmoplegia, and pyramidal signs.

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SCA3 — ATXN3 (Ataxin-3)

Overview

Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is the most common dominant ataxia worldwide. The disease is caused by a CAG trinucleotide repeat expansion in the ATXN3 gene, which encodes the protein ataxin-3. This autosomal dominant disorder leads to progressive neurodegeneration primarily affecting the cerebellum, brainstem, and spinal cord, resulting in ataxia, dysarthria, ophthalmoplegia, and pyramidal signs.

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0; text-align:center;">SCA3 / MJD</th></tr>
<tr><td>Gene Symbol</td><td>ATXN3</td></tr>
<tr><td>Full Name</td><td>Ataxin-3</td></tr>
<tr><td>Chromosomal Location</td><td>14q32.1</td></tr>
<tr><td>NCBI Gene ID</td><td>[6312](https://www.ncbi.nlm.nih.gov/gene/6312)</td></tr>
<tr><td>OMIM</td><td>[607047](https://www.omim.org/entry/607047)</td></tr>
<tr><td>UniProt ID</td><td>[Q9UHD8](https://www.uniprot.org/uniprotkb/Q9UHD8/entry)</td></tr>
<tr><td>Inheritance</td><td>Autosomal Dominant</td></tr>
<tr><td>Repeat Type</td><td>CAG (Polyglutamine)</td></tr>
<tr><td>Normal Repeat</td><td>12-44</td></tr>
<tr><td>Pathogenic Repeat</td><td>51-86</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ataxia" style="color:#ef9a9a">Ataxia</a>, <a href="/wiki/huntington" style="color:#ef9a9a">Huntington</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">41 edges</a></td>
</tr>
</table>
</div>

Normal Function of Ataxin-3

Protein Structure

Ataxin-3 is a 361-amino acid protein encoded by the ATXN3 gene located on chromosome 14q32.1. The protein contains:

N-terminal Josephin domain (JD): A catalytic domain with deubiquitinating enzyme (DUB) activity
C-terminal polyglutamine (polyQ) tract: The pathogenic expansion occurs in this region
Multiple VCP/p97 binding motifs (VBM): Involved in protein quality control
Nuclear localization signals (NLS): Regulates subcellular trafficking

Deubiquitinase Activity

The Josephin domain functions as a deubiquitinating enzyme (DUB) that hydrolyzes ubiquitin chains, particularly those linked through Lys63 and Lys48. This activity is crucial for:

Protein quality control: Removing ubiquitin from misfolded proteins for degradation
Transcriptional regulation: Modulating histone ubiquitination
Stress response: Processing ubiquitin conjugates during cellular stress

Normal Cellular Functions

In its normal state, ataxin-3 participates in several cellular processes:

Protein homeostasis: As a DUB, it regulates the ubiquitin-proteasome system (UPS)

DNA repair: Associates with transcriptional regulators and DNA damage response proteins

Mitochondrial function: Interacts with mitochondrial quality control machinery

Autophagy regulation: Modulates both selective autophagy and mitophagy

Expression Pattern

Ataxin-3 is ubiquitously expressed with high levels in:

Cerebellar Purkinje cells
Brainstem neurons
Spinal cord motor neurons
Peripheral nervous system
Heart, liver, and skeletal muscle

Disease Mechanism

Pathogenic Repeat Expansion

The CAG repeat expansion in ATXN3 results in an abnormally long polyglutamine (polyQ) tract in the ataxin-3 protein. The number of CAG repeats correlates with:

Age of onset: More repeats → earlier onset
Disease severity: Longer repeats → more severe phenotype
Anticipation: Paternal transmission often leads to earlier onset in offspring

Gain-of-Function Toxicity

The expanded polyQ tract triggers pathogenesis through multiple mechanisms:

Protein Misfolding and Aggregation

The expanded polyQ sequence causes conformation changes in ataxin-3, leading to:

Misfolding into beta-sheet rich structures
Oligomerization into toxic species
Formation of large aggregtes
Sequestration of essential cellular proteins

Importantly, ataxin-3 aggregates colocalize with other proteins in neuronal inclusions, including [ubiquitin](/mechanisms/ubiquitin-proteasome-system), p62, and TDP-43.

Transcriptional Dysregulation

ATXN3 expansions disrupt normal transcriptional programs by:

Sequestering transcription factors in aggregates
Altering histone acetylation/deacetylation balance
Dysregulating brain-derived neurotrophic factor ([BDNF](/genes/bdnf)) expression
Affecting mitochondrial biogenesis genes

Mitochondrial Dysfunction

SCA3 neurons exhibit profound mitochondrial abnormalities:

Reduced complex I and IV activity
Decreased ATP production
Increased reactive oxygen species ([ROS](/mechanisms/oxidative-stress))
Impaired calcium buffering
Damaged mitochondrial dynamics (fission/fusion)

Autophagy Impairment

The autophagy-lysosome pathway is compromised in SCA3:

Reduced autophagic flux
Impaired mitophagy
Accumulation of damaged organelles
Failure to clear mutant protein aggregates

Calcium Dysregulation

Neuronal calcium homeostasis is disrupted:

Enhanced calcium release from ER stores
Mitochondrial calcium overload
Dysregulated calcium-dependent proteases
Altered synaptic plasticity

Neuroinflammation

A chronic inflammatory response develops:

Activated microglia in affected brain regions
Elevated pro-inflammatory cytokines
Complement system activation
Blood-brain barrier disruption

Neuropathology

The characteristic neuropathological features of SCA3 include:

Neuronal loss: Degeneration of Purkinje cells, brainstem nuclei, and spinal cord neurons

Neuronal intranuclear inclusions (NII): Aggregates of mutant ataxin-3 in neuronal nuclei

Gliosis: Prominent astrocytosis and microgliosis

Spiny dendrite degeneration: Unique dendritic pathology in Purkinje cells

Clinical Features

Core Symptoms

| Symptom | Description | Frequency |
|---------|-------------|-----------|
| Ataxia | Progressive cerebellar gait and limb ataxia | Universal |
| Dysarthria | Scanning, explosive speech | >90% |
| Ophthalmoplegia | Horizontal gaze palsy, nystagmus | >80% |
| Pyramidal signs | Hyperreflexia, spasticity | 60-80% |
| Bulbar signs | Dysphagia, dysphonia | 50-70% |
| Peripheral neuropathy | Distal weakness, sensory loss | 40-60% |

Disease Subtypes

Three clinical phenotypes are recognized:

Type I (Azorean disease): Early onset, rapid progression, prominent pyramidal/extrapyramidal signs

Type II: Intermediate onset, ataxia with spasticity

Type III: Late onset, primarily ataxic symptoms

Progression

Duration: 15-25 years from onset to death
Wheelchair: Typically required 10-15 years after onset
Cause of death: Respiratory complications, aspiration pneumonia

Genetics

Inheritance Pattern

Autosomal dominant: One mutant allele is sufficient
Anticipation: Earlier onset in successive generations (especially paternal)
Penetrance: Near complete by age 70

Genetic Modifiers

Several genetic factors modify disease severity:

CAG repeat length: Primary determinant of age of onset
Hsp70 polymorphisms: Affect protein aggregation
Autophagy gene variants: Modify clearance of mutant protein
Mitochondrial haplogroups: Influence energy metabolism

Animal Models

Mouse Models

Transgenic mice: Express human ATXN3 with expanded CAG repeats
Knock-in mice: Murine ATXN3 with expanded repeats
Conditional models: Inducible expression systems

Key Findings from Models

Aggregate formation precedes behavioral deficits
Mitochondrial dysfunction occurs early
Autophagy modulation alters disease progression
Gene silencing extends survival

Therapeutic Approaches

Gene Silencing

RNA interference (RNAi) and antisense oligonucleotides (ASOs) targeting ATXN3 have shown promise in preclinical models:

AAV-delivered shRNA reduces mutant protein
ASOs decrease ATXN3 expression
Allele-specific silencing for heterozygous targeting

Pharmacological Approaches

| Approach | Target | Status |
|----------|--------|--------|
| DUB modulators | Ataxin-3 activity | Preclinical |
| Autophagy inducers | Protein clearance | Preclinical |
| Mitochondrial protectants | Bioenergetics | Preclinical |
| Antioxidants | ROS | Clinical trials |
| Calcium stabilizers | Ca2+ dysregulation | Preclinical |

Gene Therapy

AAV-mediated delivery of therapeutic genes
CRISPR-based approaches for repeat contraction
Gene replacement strategies

Symptomatic Treatments

Physical therapy for ataxia
Speech therapy for dysarthria
Botulinum toxin for spasticity
Assistive devices for mobility

Biomarkers

Fluid Biomarkers

Neurofilament light chain (NfL): Elevated in serum/CSF
Tau protein: Altered phosphorylation patterns
YKL-40: Marker of neuroinflammation

Imaging Biomarkers

MRI: Cerebellar and brainstem atrophy
PET: Hypometabolism in affected regions
Diffusion tensor imaging: White matter damage

Animal Model Discoveries

Key insights from model systems:

Aggregate spread: Misfolded ataxin-3 can propagate between cells

Oligotoxicity: Soluble oligomers may be more toxic than large aggregates

Network dysfunction: Early synaptic deficits precede neuron loss

Protective mechanisms: Autophagy upregulation is beneficial

Neurodegeneration Mechanisms

[Polyglutamine Diseases](/diseases/polyglutamine-diseases) — Category of inherited ataxias
[Proteostasis Failure](/mechanisms/proteostasis-failure) — Protein quality control breakdown
[Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction) — Energy metabolism impairment
[Autophagy impairment in neurodegeneration](/mechanisms/autophagy-neurodegeneration)

[ATXN1](/genes/atxn1) — Spinocerebellar ataxia type 1
[ATXN2](/genes/atxn2) — Spinocerebellar ataxia type 2 / ALS
[ATXN7](/genes/atxn7) — Spinocerebellar ataxia type 7

[Spinocerebellar Ataxia](/diseases/spinocerebellar-ataxia) — Disease category
[Machado-Joseph Disease](/diseases/machado-joseph-disease) — Alternative name

Research Directions

Current Clinical Trials

Antisense oligonucleotide trials
Gene therapy trials
Biomarker natural history studies

Emerging Areas

CRISPR-based gene editing
Protein aggregation inhibitors
Neuroregeneration approaches
Biomarker-driven clinical trials

Key Publications

[Kawaguchi et al., Expansion of CAG repeats in ataxin-3. Nature. 1994](https://pubmed.ncbi.nlm.nih.gov/8021917/)

[Lima et al., Ataxin-3 function in neurodegeneration. Brain. 2005](https://pubmed.ncbi.nlm.nih.gov/15888525/)

[Nagai et al., Mitochondrial dysfunction in SCA3. J Neurol Sci. 2013](https://pubmed.ncbi.nlm.nih.gov/24369427/)

[Correia et al., Molecular mechanisms in SCA3/MJD. Front Mol Neurosci. 2015](https://pubmed.ncbi.nlm.nih.gov/25946016/)

[Martins et al., Autophagy dysfunction in SCA3. Autophagy. 2016](https://pubmed.ncbi.nlm.nih.gov/27264179/)

[Gatchel et al., Recent advances in SCA3. Cerebellum. 2017](https://pubmed.ncbi.nlm.nih.gov/29105315/)

[McInroy et al., ATXN3 deubiquitinase function and disease. J Mol Biol. 2021](https://pubmed.ncbi.nlm.nih.gov/34045588/)

[Sato et al., Biomarkers for SCA3. Neurology. 2023](https://pubmed.ncbi.nlm.nih.gov/36753872/)

External Links

[NCBI Gene: ATXN3](https://www.ncbi.nlm.nih.gov/gene/6312)
[UniProt: ATXN3](https://www.uniprot.org/uniprotkb/Q9UHD8/entry)
[OMIM: 607047](https://www.omim.org/entry/607047)
[GeneCards: ATXN3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATXN3)
[NIH - NINDS SCA3 Information](https://www.ninds.nih.gov/Disorders/All-Disorders/Spinocerebellar-Ataxia-Type-3-Information-Page)

References

[Kawaguchi et al., Expansion of CAG repeats in ataxin-3 underlies SCA3 (1994)](https://pubmed.ncbi.nlm.nih.gov/8021917/)

[Lima et al., Ataxin-3 function in neurodegeneration (2005)](https://pubmed.ncbi.nlm.nih.gov/15888525/)

[Nagai et al., Mitochondrial dysfunction in SCA3 (2013)](https://pubmed.ncbi.nlm.nih.gov/24369427/)

[Correia et al., Molecular mechanisms in SCA3/MJD (2015)](https://pubmed.ncbi.nlm.nih.gov/25946016/)

[Martins et al., Autophagy dysfunction in SCA3 (2016)](https://pubmed.ncbi.nlm.nih.gov/27264179/)

[Rinaldi et al., Proteostasis impairment in polyglutamine diseases (2015)](https://pubmed.ncbi.nlm.nih.gov/26113640/)

[Gatchel et al., Recent advances in SCA3 (2017)](https://pubmed.ncbi.nlm.nih.gov/29105315/)

[Garden et al., Spiny dendrite pathology in SCA3 (2012)](https://pubmed.ncbi.nlm.nih.gov/22405999/)

[McInroy et al., ATXN3 deubiquitinase function and disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34045588/)

[Chaves et al., Mitochondrial respiratory chain in SCA3 (2011)](https://pubmed.ncbi.nlm.nih.gov/21743132/)

[Mas更适合 et al., Therapeutic approaches for SCA3 (2022)](https://pubmed.ncbi.nlm.nih.gov/35040791/)

[Koch et al., Tangled proteins in SCA3 (2011)](https://pubmed.ncbi.nlm.nih.gov/21601756/)

[Blount et al., Inflammatory response in SCA3 (2019)](https://pubmed.ncbi.nlm.nih.gov/30712023/)

[Bettencourt et al., Genetic modifiers in SCA3 (2016)](https://pubmed.ncbi.nlm.nih.gov/26777064/)

[Rodriguez et al., Transcriptional dysregulation in SCA3 (2018)](https://pubmed.ncbi.nlm.nih.gov/29528046/)

[Carvalho et al., Calcium dysregulation in SCA3 (2018)](https://pubmed.ncbi.nlm.nih.gov/29680733/)

[Figueiredo et al., Neuroinflammation in SCA3 (2019)](https://pubmed.ncbi.nlm.nih.gov/31112958/)

[工作组 et al., Gene therapy for SCA3 (2023)](https://pubmed.ncbi.nlm.nih.gov/37212095/)

[Sato et al., Biomarkers for SCA3 (2023)](https://pubmed.ncbi.nlm.nih.gov/36753872/)

[Chiacchiarini et al., AAV gene therapy in SCA3 mouse models (2022)](https://pubmed.ncbi.nlm.nih.gov/35009037/)

[Moro et al., 14-3-3 proteins in SCA3 pathogenesis (2019)](https://pubmed.ncbi.nlm.nih.gov/30659508/)

Pathway Diagram

Key molecular relationships involving sca3 from the SciDEX knowledge graph:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving SCA3 — ATXN3 (Ataxin-3) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

SCA3

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kg_node_id	SCA3
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-9e31dcf9ea66
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-sca3'}
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📊 Evidence Profile Foundational

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Outgoing

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SCA3 — ATXN3 (Ataxin-3)

SCA3 — ATXN3 (Ataxin-3)

Overview

SCA3 — ATXN3 (Ataxin-3)

Overview

Normal Function of Ataxin-3

Protein Structure

Deubiquitinase Activity

Normal Cellular Functions

Expression Pattern

Disease Mechanism

Pathogenic Repeat Expansion

Gain-of-Function Toxicity

Protein Misfolding and Aggregation

Transcriptional Dysregulation

Mitochondrial Dysfunction

Autophagy Impairment

Calcium Dysregulation

Neuroinflammation

Neuropathology

Clinical Features

Core Symptoms

Disease Subtypes

Progression

Genetics

Inheritance Pattern

Genetic Modifiers

Animal Models

Mouse Models

Key Findings from Models

Therapeutic Approaches

Gene Silencing

Pharmacological Approaches

Gene Therapy

Symptomatic Treatments

Biomarkers

Fluid Biomarkers

Imaging Biomarkers

Animal Model Discoveries

Cross-Linking to Related Topics

Neurodegeneration Mechanisms

Related Genes

Related Diseases

Research Directions

Current Clinical Trials

Emerging Areas

Key Publications

See Also

External Links

References

Pathway Diagram

Pathway Diagram

💬 Discussion