Proteasome degrades soluble expanded polyglutamine completely and efficiently.

To date, nine progressive neurodegenerative diseases are caused by expansion of the CAG repeat coding for polyglutamine, including Huntington's disease and several forms of spinocerebellar ataxia. Expanded polyglutamine causes dominant toxic gain-of-function related to its ability to aggregate. Polyglutamine aggregates inhibit the proteasome, suggesting that reduced degradation of misfolded proteins might contribute to polyglutamine toxicity. Moreover, several observations indicate that soluble proteins harboring expanded polyglutamine display altered turnover. To examine whether soluble polyglutamine interfered with proteasome-mediated degradation, we analyzed degradation of model proteasome substrates carrying either 103 or 25 glutamines in transfected cells. Expanded and normal size polyglutamine were degraded to completion and with similar efficiency. Moreover, targeting of expanded polyglutamine for proteasome-mediated degradation did not compromise proteasome activity. Thus, we propose that polyglutamine-containing disease proteins can be readily digested by the proteasome if they carried a degradation signal.