ATXN3

ATXN3 is a human gene that encodes ataxin-3, a deubiquitinating enzyme involved in the ubiquitin-proteasome system. The protein contains an N-terminal Josephin domain with proteolytic activity and C-terminal ubiquitin-interacting motifs. It also harbors a polyglutamine (polyQ) tract whose length varies among individuals.

Normal ATXN3 alleles typically have a polyQ repeat length in the range of about 12 to 44. Pathogenic disease-causing expansions are longer, generally exceeding 55 repeats, and show anticipation with increasing repeat length. Inheritance is autosomal dominant. Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, results from expanded CAG repeats in ATXN3 and is one of the most common dominantly inherited ataxias in many populations.

SCA3 presents as a progressive neurodegenerative disorder with cerebellar symptoms such as gait imbalance, ataxia, dysarthria, and in some cases oculomotor abnormalities. Non-ataxia features can include parkinsonism, dystonia, pyramidal signs, and peripheral neuropathy. Age of onset is usually in adulthood but can vary; disease progression is gradual and heterogeneous.

Pathophysiology involves a gain-of-function effect from the polyQ-expanded ataxin-3, which tends to misfold and form intracellular aggregates. These aggregates disrupt proteostasis and ubiquitin signaling, contributing to neuronal dysfunction and loss, particularly in the cerebellum and brainstem.

Diagnosis is confirmed by genetic testing showing an expanded ATXN3 CAG repeat. There is no cure; management is supportive and multidisciplinary. Research efforts include gene-silencing approaches (such as antisense oligonucleotides or RNA interference) and strategies to reduce aggregation or enhance clearance of mutant ataxin-3.