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J. Cell Biol. 170 (7): 1101-1111

Copyright © 2005 by the Rockefeller University Press.

Article

Lithium induces autophagy by inhibiting inositol monophosphatase

Sovan Sarkar1, R. Andres Floto2, Zdenek Berger1,3, Sara Imarisio1,3, Axelle Cordenier1,3, Matthieu Pasco3, Lynnette J. Cook1, , and David C. Rubinsztein1

1 Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2XY, England, UK
2 Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2XY, England, UK
3 Department of Genetics, University of Cambridge, Cambridge CB2 3EH, England, UK

Correspondence to David C. Rubinsztein: dcr1000{at}hermes.cam.ac.uk

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 3ß 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.

Abbreviations used in this paper: 3-MA, 3-methyladenine; 4E-BP1, eukaryotic initiation factor 4E-binding protein 1; CBZ, carbamazepine; EGFP-HDQ74, EGFP-tagged huntingtin exon 1 with 74 polyglutamine repeats; GSK-3ß, glycogen synthase kinase 3ß; HD, Huntington's disease; IMPase, inositol monophosphatase; IP1-2, inositol mono- and bis-phosphate; IP3, myo-inositol-1,4,5-triphosphate; LC3, microtubule-associated protein 1 light chain 3; mTOR, mammalian target of rapamycin; PD, Parkinson's disease; PEI, prolyl endopeptidase inhibitor; S6P, ribosomal S6 protein.

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