Novel targets for Huntington's disease in an mTOR-independent autophagy pathway.
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.
Williams
Andrea
A
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Sarkar
Sovan
S
Cuddon
Paul
P
Ttofi
Evangelia K
EK
Saiki
Shinji
S
Siddiqi
Farah H
FH
Jahreiss
Luca
L
Fleming
Angeleen
A
Pask
Dean
D
Goldsmith
Paul
P
O'Kane
Cahir J
CJ
Floto
Rodrigo Andres
RA
Rubinsztein
David C
DC
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
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