The ATXN8 gene (Ataxin-8) encodes a polyglutamine (polyQ) expansion protein that causes spinocerebellar ataxia type 8 (SCA8) when the CAG trinucleotide repeat expands abnormally. SCA8 is a progressive cerebellar ataxia characterized by slowly progressive incoordination, speech difficulties, and various neurological manifestations. The ataxin-8 protein is widely expressed in the nervous system and has complex normal functions that are disrupted by polyQ expansion.
| Attribute |
Value |
| Gene Symbol |
ATXN8 |
| Full Name |
Ataxin-8 |
| Chromosomal Location |
13q21 |
| NCBI Gene ID |
6315 |
| Ensembl ID |
ENSG00000174187 |
| UniProt ID |
Q9UQ72 |
| Gene Type |
Protein coding |
| OMIM |
603680 |
Ataxin-8 is a protein of approximately 343 amino acids in its normal form. The protein contains a polyglutamine (polyQ) tract near its N-terminus, which becomes pathologically expanded in SCA8. The length of the polyQ tract determines disease onset and severity.
- PolyQ Tract: N-terminal glutamine repeats (normal: 17-50, pathogenic: 71-1300+)
- Axin Domain: Involved in protein-protein interactions
- Nuclear Localization Signals: Potential nuclear function
- HEAT Repeats: Protein interaction motifs
Normal ataxin-8 functions are not fully understood, but research suggests:
- Transcriptional Regulation: May modulate gene expression
- Cell Signaling: Involved in various signaling pathways
- Neuronal Development: Important for proper brain development
- RNA Processing: Some evidence for RNA-binding capability
- Synaptic Function: May affect neurotransmitter release
- Broad expression in central nervous system
- High expression in cerebellum
- Present in Purkinje cells
- Found in cerebral cortex and brainstem
SCA8 is an autosomal dominant trinucleotide repeat disorder:
- Onset: Usually adulthood (30-40 years)
- Progression: Slowly progressive over decades
- Symptoms: Ataxia, dysarthria, nystagmus, weakness
- Repeat Length: Correlation with age of onset
- Essential Tremor: Some association with ATXN8 variants
- Parkinson's Disease: Possible interaction with PD risk
- Schizophrenia: Rare genetic associations investigated
| Repeat Length |
Effect |
| 17-50 |
Normal range |
| 51-70 |
Intermediate (reduced penetrance) |
| 71-1300 |
Pathogenic (SCA8) |
- Toxic Gain-of-Function: Expanded polyQ protein acquires new toxic properties
- RNA Toxicity: Toxic RNA from expanded repeat may contribute
- Protein Aggregation: Forms neuronal inclusions
- Transcriptional Dysregulation: Affects gene expression
- Gene Silencing: ASO and siRNA approaches targeting ATXN8
- Protein Aggregation Modulators: Compounds that reduce aggregation
- Neuroprotective Agents: General neuroprotective strategies
- Antisense Oligonucleotides: In development for gene silencing
- CRISPR-based Therapies: Gene editing approaches
- Small Molecule Modulators: Aggregation inhibitors
- Cell Replacement Therapy: Potential for regenerative approaches
- Late disease onset complicates clinical trials
- Repeat length variability
- Need for biomarkers
- Brain delivery of therapeutics
| Partner |
Interaction |
| ATXN8OS |
Overlapping transcript |
| TBP |
TATA-binding protein |
| REST |
Transcriptional regulator |
| Various transcription factors |
Modulated by ataxin-8 |
- Overlapping Transcripts: ATXN8OS and ATXN8 share genomic space
- Antisense Transcripts: Bidirectional expression
- Genetic Modifiers: Other genes may modify SCA8 phenotype
- Transcriptional regulation
- RNA processing
- Protein quality control
- Cellular stress response
Current research focuses on:
- Understanding normal ataxin-8 function
- Developing gene-silencing therapeutics
- Identifying biomarkers
- Exploring neuroprotective strategies
- Understanding RNA toxicity mechanisms