PT - JOURNAL ARTICLE AU - Matthew A. King AU - Sarah Hands AU - Farida Hafiz AU - Noboru Mizushima AU - Aviva M. Tolkovsky AU - Andreas Wyttenbach TI - Rapamycin Inhibits Polyglutamine Aggregation Independently of Autophagy by Reducing Protein Synthesis AID - 10.1124/mol.107.043398 DP - 2008 Apr 01 TA - Molecular Pharmacology PG - 1052--1063 VI - 73 IP - 4 4099 - http://molpharm.aspetjournals.org/content/73/4/1052.short 4100 - http://molpharm.aspetjournals.org/content/73/4/1052.full SO - Mol Pharmacol2008 Apr 01; 73 AB - Accumulation of misfolded proteins and protein assemblies is associated with neuronal dysfunction and death in several neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease (HD). It is therefore critical to understand the molecular mechanisms of drugs that act on pathways that modulate misfolding and/or aggregation. It is noteworthy that the mammalian target of rapamycin inhibitor rapamycin or its analogs have been proposed as promising therapeutic compounds clearing toxic protein assemblies in these diseases via activation of autophagy. However, using a cellular model of HD, we found that rapamycin significantly decreased aggregation-prone polyglutamine (polyQ) and expanded huntingtin and its inclusion bodies (IB) in both autophagy-proficient and autophagy-deficient cells (by genetic knockout of the atg5 gene in mouse embryonic fibroblasts). This result suggests that rapamycin modulates the levels of misfolded polyQ proteins via pathways other than autophagy. We show that rapamycin reduces the amount of soluble polyQ protein via a modest inhibition of protein synthesis that in turn significantly reduces the formation of insoluble polyQ protein and IB formation. Hence, a modest reduction in huntingtin synthesis by rapamycin may lead to a substantial decrease in the probability of reaching the critical concentration required for a nucleation event and subsequent toxic polyQ aggregation. Thus, in addition to its beneficial effect proposed previously of reducing polyQ aggregation/toxicity via autophagic pathways, rapamycin may alleviate polyQ disease pathology via its effect on global protein synthesis. This finding may have important therapeutic implications. The American Society for Pharmacology and Experimental Therapeutics