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 a-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.Addendum to:Lithium induces autophagy by inhibiting inositol monophosphataseS. Sarkar, R.A. Floto, Z. Berger, S. Imarisio, A. Cordenier, M. Pasco, L.J. Cook, D.C. RubinszteinJ Cell Biol 2005; 170:1101-11.