Article abstract
Nature Chemical Biology 4, 295 - 305 (2008)
Published online: 23 March 2008 | doi:10.1038/nchembio.79
Novel targets for Huntington's disease in an mTOR-independent autophagy pathway
Andrea Williams1,6, Sovan Sarkar1,6, Paul Cuddon1,2,6, Evangelia K Ttofi1,3, Shinji Saiki1, Farah H Siddiqi1, Luca Jahreiss1, Angeleen Fleming2, Dean Pask2, Paul Goldsmith4, Cahir J O'Kane3, Rodrigo Andres Floto5 & David C Rubinsztein1
Abstract
Autophagy is a major clearance route for intracellular aggregate-prone proteins causing diseases such as Huntington's disease. Autophagy induction with the mTOR inhibitor rapamycin accelerates clearance of these toxic substrates. As rapamycin has nontrivial side effects, we screened FDA-approved drugs to identify new autophagy-inducing pathways. We found that L-type Ca2+ channel antagonists, the K+ATP channel opener minoxidil, and the Gi signaling activator clonidine induce autophagy. These drugs revealed a cyclical mTOR-independent pathway regulating autophagy, in which cAMP regulates IP3 levels, influencing calpain activity, which completes the cycle by cleaving and activating Gs
, which regulates cAMP levels. This pathway has numerous potential points where autophagy can be induced, and we provide proof of principle for therapeutic relevance in Huntington's disease using mammalian cell, fly and zebrafish models. Our data also suggest that insults that elevate intracytosolic Ca2+ (like excitotoxicity) inhibit autophagy, thus retarding clearance of aggregate-prone proteins.
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
- Summit plc, 7340 Cambridge Research Park, Beach Drive, Waterbeach, Cambridge CB25 9TN, UK.
- Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
- Department of Neurology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
- Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
- These authors contributed equally to this work.
Correspondence to: David C Rubinsztein1 e-mail: dcr1000@hermes.cam.ac.uk
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