title: Lithium induces autophagy by inhibiting inositol monophosphatase.
abstract: Macroautophagy is a key pathway for the clearance of aggregate-prone cytosolic proteins. Currently, the only suitable pharmacologic strategy for up-regulating autophagy in mammalian cells is to use rapamycin, which inhibits the mammalian target of rapamycin (mTOR), a negative regulator of autophagy. Here we describe a novel mTOR-independent pathway that regulates autophagy. We show that lithium induces autophagy, and thereby, enhances the clearance of autophagy substrates, like mutant huntingtin and alpha-synucleins. This effect is not mediated by glycogen synthase kinase 3beta inhibition. The autophagy-enhancing properties of lithium were mediated by inhibition of inositol monophosphatase and led to free inositol depletion. This, in turn, decreased myo-inositol-1,4,5-triphosphate (IP3) levels. Our data suggest that the autophagy effect is mediated at the level of (or downstream of) lowered IP3, because it was abrogated by pharmacologic treatments that increased IP3. This novel pharmacologic strategy for autophagy induction is independent of mTOR, and may help treatment of neurodegenerative diseases, like Huntington's disease, where the toxic protein is an autophagy substrate.
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2XY, England, UK.
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.forename: R Andres
authors.initials: RA
authors.lastname: Floto
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Berger
authors.forename: Sara
authors.initials: S
authors.lastname: Imarisio
authors.forename: Axelle
authors.initials: A
authors.lastname: Cordenier
authors.forename: Matthieu
authors.initials: M
authors.lastname: Pasco
authors.forename: Lynnette J
authors.initials: LJ
authors.lastname: Cook
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000071058:Huntingtin Protein; D007294:Inositol / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051844:alpha-Synuclein; D007294:Inositol; D008094:Lithium; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D020123:Sirolimus