title: Novel targets for Huntington's disease in an mTOR-independent autophagy pathway.
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 G(i) 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 G(s)alpha, 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.
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Williams
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.forename: Paul
authors.initials: P
authors.lastname: Cuddon
authors.forename: Evangelia K
authors.initials: EK
authors.lastname: Ttofi
authors.forename: Shinji
authors.initials: S
authors.lastname: Saiki
authors.forename: Farah H
authors.initials: FH
authors.lastname: Siddiqi
authors.forename: Luca
authors.initials: L
authors.lastname: Jahreiss
authors.forename: Angeleen
authors.initials: A
authors.lastname: Fleming
authors.forename: Dean
authors.initials: D
authors.lastname: Pask
authors.forename: Paul
authors.initials: P
authors.lastname: Goldsmith
authors.forename: Cahir J
authors.initials: CJ
authors.lastname: O'Kane
authors.forename: Rodrigo Andres
authors.initials: RA
authors.lastname: Floto
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000276:immunology / Q000503:physiopathology*; D054755:Imidazoline Receptors / Q000037:antagonists & inhibitors; D008914:Minoxidil / Q000494:pharmacology; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D010738:Type C Phospholipases / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020746:Calcium Channels, L-Type; D054755:Imidazoline Receptors; C410887:imidazoline I1 receptors; D008914:Minoxidil; D014700:Verapamil; D000242:Cyclic AMP; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D010738:Type C Phospholipases; D003000:Clonidine