Rapamycin inhibits polyglutamine aggregation independently of autophagy by reducing protein synthesis

Accumulation of misfolded proteins and protein assemblies is associated with neuronal dysfunction and death in several neu-rodegenerative 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 clear-ing 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 polyglu-tamine (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 fibro