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J Exp Neurosci. 2016 May 5;9(Suppl 2):123-9. doi: 10.4137/JEN.S25469. eCollection 2015.

Stabilization and Degradation Mechanisms of Cytoplasmic Ataxin-1.

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B.A., Skidmore College Neuroscience Program, Saratoga Springs, NY, USA.
Assistant Professor of Neuroscience, Williamson Chair in Neuroscience, Skidmore College Neuroscience Program, Saratoga Springs, NY, USA.


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.


14-3-3; Ataxin-1; aggregation; autophagy; mTOR; nuclear inclusions; spinocerebellar ataxia type 1; ubiquitin proteasome system

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