title: Stabilization and Degradation Mechanisms of Cytoplasmic Ataxin-1.
abstract: Aggregation-prone proteins in neurodegenerative disease disrupt cellular protein stabilization and degradation pathways. The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is caused by a coding polyglutamine expansion in the Ataxin-1 gene (ATXN1), which gives rise to the aggregation-prone mutant form of ATXN1 protein. Cerebellar Purkinje neurons, preferentially vulnerable in SCA1, produce ATXN1 protein in both cytoplasmic and nuclear compartments. Cytoplasmic stabilization of ATXN1 by phosphorylation and 14-3-3-mediated mechanisms ultimately drive translocation of the protein to the nucleus where aggregation may occur. However, experimental inhibition of phosphorylation and 14-3-3 binding results in rapid degradation of ATXN1, thus preventing nuclear translocation and cellular toxicity. The exact mechanism of cytoplasmic ATXN1 degradation is currently unknown; further investigation of degradation may provide future therapeutic targets. This review examines the present understanding of cytoplasmic ATXN1 stabilization and potential degradation mechanisms during normal and pathogenic states.
authors.affiliation: B.A., Skidmore College Neuroscience Program, Saratoga Springs, NY, USA.
authors.forename: Mayumi F
authors.initials: MF
authors.lastname: Kohiyama
authors.affiliation: Assistant Professor of Neuroscience, Williamson Chair in Neuroscience, Skidmore College Neuroscience Program, Saratoga Springs, NY, USA.
authors.forename: Sarita
authors.initials: S
authors.lastname: Lagalwar
keywords: 14-3-3; Ataxin-1; aggregation; autophagy; mTOR; nuclear inclusions; spinocerebellar ataxia type 1; ubiquitin proteasome system