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Article Addendum

Amelioration of protein misfolding disease by rapamycin: Translation or autophagy?

Andreas Wyttenbach, Sarah Hands, Matthew A. King, Karen Lipkow and Aviva M. Tolkovsky

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Rapamycin is an inhibitor of mTOR, a key component of the mTORC1 complex that controls the growth and survival of cells in response to growth factors, nutrients, energy balance and stresses. The downstream targets of mTORC1 include ribosome biogenesis, transcription, translation and macroautophagy. Recently it was proposed that rapamycin and its derivatives enhance the clearance (and/or reduce the accumulation) of mutant intracellular proteins causing proteinopathies such as tau, α-synuclein, ataxin-3, and full-length or fragments of huntingtin containing a polyglutamine (polyQ) expansion, by up-regulating macroautophagy. We tested this proposal directly using macroautophagy-deficient fibroblasts. We found that rapamycin inhibits the aggregation of a fragment of huntingtin (exon 1) containing 97 polyQs similarly in macroautophagy-proficient (Atg5^+/+) and macroautophagy-deficient (Atg5^-/-) cells. These data demonstrate that autophagy is not the only mechanism by which rapamycin can alleviate the accumulation of misfolded proteins. Our data suggest that rapamycin inhibits mutant huntingtin fragment accumulation due to inhibition of protein synthesis. A model illustrates how a modest reduction in polyQ synthesis can lead to a long-lasting reduction in polyQ aggregation. We propose that several mechanisms exist by which rapamycin reduces the accumulation and potentially, in turn, the potential toxicity of misfolded proteins in diseases caused by protein misfolding and aggregation.

Addendum to: King MA, Hands S, Hafiz, Mizushima N, Tolkovsky A, Wyttenbach A. Rapamycin inhibits polyglutamine aggregation independently of autophagy by reducing protein synthesis. Mol Pharmacol 2008; 73:1-12.

Authors

Andreas Wyttenbach

Southampton Neuroscience Group

Sarah Hands

University of Southampton

Matthew A. King

University of Cambridge

Karen Lipkow

University of Cambridge

Aviva M. Tolkovsky

University of Cambridge

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