Lithium Decreases IP 3 to Promote Autophagy

Abstract

Lithium is widely known for its application in the treatment of bipolar and unipolar mood disorders. Sarkar et al. provide evidence that lithium may also be effective in the treatment of neurodegenerative disorders arising from toxicity of the accumulation of aggregate-prone proteins, such as mutant huntingtin and mutant α-synuclein, which are implicated in Huntington's disease and certain forms of Parkinson's disease. Stimulation of autophagy may be a mechanism to prevent the accumulation of these aggegrate-prone proteins, and Sarkar et al. show that lithium promotes autophagy, detected as an increase in the formation of autophagic vesicles and a decrease in the abundance of known autophagic substrates. Furthermore, lithium decreased the accumulation of mutant α-synuclein or huntingtin aggregates and the toxicity (cell death) of these proteins in inducible PC12 cell lines or COS-7 cell lines, an effect that was blocked by the autophagic inhibitor 3-methyladenine (3-MA). Lithium is a nonspecific inhibitor of several enzymes. The effect on autophagy appeared to be mediated by the inhibition of inositol monophosphatase (IMPase), because autophagy and clearance of mutant huntingtin and α-synuclein was also stimulated by inhibition of IMPase with a specific pharmacologic agent (L-690,330), whereas selective inhibition of glycogen synthase kinase-3β (GSK-3β, another lithium target) did not promote clearance of the aggregate-prone proteins. Both L-690,330 and lithium decreased inositol-1,4,5-trisphosphate (IP 3 ) concentrations. That lithium exerted its effects on autophagy through decreased IP 3 concentrations was validated by experiments in which IP 3 concentrations were increased before lithium treatment by addition of myo-inositol or prolyl endopeptidase inhibitor 2 (PEI). Increased IP 3 concentration promoted the accumulation of mutant huntingtin and cell death and blocked the effects of lithium to reduce these phenomena. Autophagy is also stimulated by inhibition of mTOR (mammalian target of rapamycin); however, lithium appeared to act independently from the pathway regulated by mTOR, because inhibition of mTOR with rapamycin combined with lithium had an additive effect on clearance of the aggregate-prone proteins and cell survival. The ability of lithium to stimulate autophagy and clearance of aggregate-prone proteins was also observed for other mood-stabilizing drugs that promote inositol depletion. Thus, a pathway involving IP 3 and inositol appears to be one mechanism regulating autophagy that may be exploited for therapeutic benefit in certain neurodegenerative diseases. S. Sarkar, A. Floto, Z. Berger, S. Imarisio, A. Cordenier, M. Pasco, L. J. Cook, D. C. Rubinsztein, Lithium induces autophage by inhibiting inositol monophosphate. J. Cell Biol. 170 , 1101-1111 (2005). [Abstract] [Full Text]