ataxin3

Ataxin-3 is a human protein encoded by the ATXN3 gene. It is a deubiquitinating enzyme that participates in ubiquitin-dependent protein quality control. The protein contains an N-terminal catalytic Josephin domain responsible for protease activity and a C-terminal region with a ubiquitin-interacting motif that mediates binding to ubiquitin chains. The normal function of ataxin-3 includes trimming polyubiquitin chains from substrates and regulating protein turnover; its activity influences protein homeostasis in the cytoplasm and nucleus.

Genetics and disease: An expanded CAG trinucleotide repeat in ATXN3 causes spinocerebellar ataxia type 3 (SCA3), also called Machado-Joseph disease. Normal alleles typically have 12-44 repeats; pathogenic expansions commonly exceed ~60 repeats and result in an extended polyglutamine tract in ataxin-3.

Pathology and symptoms: The polyglutamine-expanded ataxin-3 misfolds and forms intracellular inclusions; neurons throughout the CNS, especially in the cerebellum and brainstem, are affected, leading to progressive gait ataxia, dysarthria, nystagmus, and sometimes dystonia or parkinsonism. The disease is autosomal dominant with variable age of onset, often in adulthood; progression leads to increasing disability over time.

Diagnosis and management: Diagnosis is established by genetic testing to determine ATXN3 CAG repeat length. Neuroimaging may show cerebellar and brainstem atrophy. There is no cure; treatment is supportive, including physical therapy, speech therapy, and management of movement disorders. Research includes approaches to lower mutant ataxin-3 expression or enhance protein quality control.

Epidemiology and research: SCA3 is among the more common dominantly inherited spinocerebellar ataxias globally, with higher prevalence in certain populations due to founder effects. Model organisms and cell models are used to study pathogenesis and test therapies.