A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin.
Huntington's disease (HD) is caused by a polyglutamine expansion mutation in the huntingtin protein that confers a toxic gain-of-function and causes the protein to become aggregate-prone. Aggregate-prone proteins are cleared by macroautophagy, and upregulating this process by rapamycin, which inhibits the mammalian target of rapamycin (mTOR), attenuates their toxicity in various HD models. Recently, we demonstrated that lithium induces mTOR-independent autophagy by inhibiting inositol monophosphatase (IMPase) and reducing inositol and IP3 levels. Here we show that glycogen synthase kinase-3beta (GSK-3beta), another enzyme inhibited by lithium, has opposite effects. In contrast to IMPase inhibition that enhances autophagy, GSK3beta inhibition attenuates autophagy and mutant huntingtin clearance by activating mTOR. In order to counteract the autophagy inhibitory effects of mTOR activation resulting from lithium treatment, we have used the mTOR inhibitor rapamycin in combination with lithium. This combination enhances macroautophagy by mTOR-independent (IMPase inhibition by lithium) and mTOR-dependent (mTOR inhibition by rapamycin) pathways. We provide proof-of-principle for this rational combination treatment approach in vivo by showing greater protection against neurodegeneration in an HD fly model with TOR inhibition and lithium, or in HD flies treated with rapamycin and lithium, compared with either pathway alone.
Sarkar
Sovan
S
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Krishna
Gauri
G
Imarisio
Sara
S
Saiki
Shinji
S
O'Kane
Cahir J
CJ
Rubinsztein
David C
DC
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy*; D007294:Inositol / Q000096:biosynthesis; D018020:Lithium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D029721:Drosophila Proteins; D018020:Lithium Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D007294:Inositol; D011494:Protein Kinases; C416303:target of rapamycin protein, Drosophila; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D020123:Sirolimus