ATXN3

ATXN3

ATXN3 (Ataxin-3) is a protein encoded by the ATXN3 gene in humans. It is primarily known for its role in the neurodegenerative disorder known as Spinocerebellar ataxia type 3 (SCA3), also referred to as Machado-Joseph disease.

Structure

The ATXN3 protein is composed of 361 amino acids and contains a polyglutamine tract, which is a sequence of glutamine residues. The length of this polyglutamine tract can vary, and expansions beyond a certain threshold are associated with disease.

Function

ATXN3 is a deubiquitinating enzyme, meaning it is involved in the removal of ubiquitin from proteins. This activity is crucial for protein homeostasis, as ubiquitination typically marks proteins for degradation via the proteasome pathway. ATXN3 is involved in various cellular processes, including transcriptional regulation, protein quality control, and response to cellular stress.

Pathology

Mutations in the ATXN3 gene, specifically expansions of the CAG repeat that encode the polyglutamine tract, lead to the production of an abnormally long polyglutamine sequence in the ATXN3 protein. This results in the formation of toxic protein aggregates in neurons, particularly affecting the cerebellum, brainstem, and spinal cord. The accumulation of these aggregates is a hallmark of Spinocerebellar ataxia type 3, leading to progressive motor dysfunction, ataxia, and other neurological symptoms.

Clinical Significance

Spinocerebellar ataxia type 3 is the most common form of autosomal dominant ataxia worldwide. Symptoms typically begin in mid-adulthood and include gait ataxia, dysarthria, and oculomotor abnormalities. As the disease progresses, patients may experience spasticity, dystonia, and peripheral neuropathy.

Research and Therapeutic Approaches

Research into ATXN3 and SCA3 is ongoing, with efforts focused on understanding the molecular mechanisms of disease and developing potential therapies. Approaches under investigation include gene silencing techniques, such as RNA interference and antisense oligonucleotides, as well as small molecules that may modulate protein aggregation or enhance protein clearance.

Also see

• Spinocerebellar ataxia
• Polyglutamine diseases
• Ubiquitin-proteasome system
• Neurodegenerative disorders