Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations.
We recently showed that lithium induces autophagy via inositol monophosphatase (IMPase) inhibition, leading to free inositol depletion and reduced myo-inositol-1,4, 5-triphosphate (IP3) levels. This represents a novel way of regulating mammalian autophagy, independent of the mammalian target of rapamycin (mTOR). Induction of autophagy by lithium led to enhanced clearance of autophagy substrates, like mutant huntingtin fragments and mutant alpha-synucleins, associated with Huntington's disease (HD) and some autosomal dominant forms of Parkinson's disease (PD), respectively. Similar effects were observed with a specific IMPase inhibitor and mood-stabilizing drugs that decrease inositol levels. This may represent a new therapeutic strategy for upregulating autophagy in the treatment of neurodegenerative disorders, where the mutant protein is an autophagy substrate. In this Addendum, we review these findings, and some of the speculative possibilities they raise.
Sarkar
Sovan
S
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, UK.
Rubinsztein
David C
DC
D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D004164:Diphosphonates / Q000494:pharmacology; D000071058:Huntingtin Protein; D007294:Inositol / Q000378:metabolism*; D018020:Lithium Compounds / Q000627:therapeutic use; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D004164:Diphosphonates; C086055:HTT protein, human; D000071058:Huntingtin Protein; D018020:Lithium Compounds; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051844:alpha-Synuclein; C079103:L 690330; D007294:Inositol; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase