Stabilization and Degradation Mechanisms of Cytoplasmic Ataxin-1

Mayumi F. Kohiyama ； Sarita Lagalwar

《Journal of Experimental Neuroscience》 2015-S2期 (2015/12) Pp. 123-129

https://doi.org/10.4137/JEN.S25469

並列摘要

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.

並列關鍵字

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