Lithium induces autophagy by inhibiting inositol monophosphatase

Sarkar, S. et al.  Cell Biol. 170: 1101-1111, 2005.

Speaker: 呂秀菱                  Time: 21-Dec-2005 15:10~16:00

Commentator: 劉校生 老師         Place: Room 601

Abstract :

    There are three classes of cell death including autophagy, which plays other important role in regulating cell survival and long-lived proteins degradation to maintain cell homeostasis.¹ Huntington’s disease (HD) and Parkinson’s disease (PD) are neurodegenerative diseases which are related with toxic-protein aggregation, like mutant huntingtin and A53T, A30P mutant forms of α-synucleins, can cause neuron cell death. Rapamycin is the only pharmacologic strategy for up-regulating autophagy through inhibiting mTOR pathway. Previous study showed that lithium, a common drug used for mood stabilizer, could reduce mutant protein aggregates and cell death.² However, the mechanism of clearance of aggregating proteins by lithium is not fully understood. In this study, the authors found that lithium induced autophagy through a mTOR-independent pathway. The autophagy-enhancing properties of lithium were mediated by inhibition of inositol monophosphatase (IMPase), but not glycogen synthase kinas-3β (GSK-3β), which led to reduction of free inositol and myo-inositol-1,4,5-triphosphate (IP₃) levels. Furthermore, increasing the levels of inositol and IP₃ by pretreatment with myo-inositol and prolyl endopeptidase inhibitor (PEI), respectively, induced mutant protein aggregation and cell death. Therefore, the effect of lithium on clearance of mutant proteins is regulated by IP₃ levels. Inhibition of IMPase and mTOR activity by lithium and rapamycin simultaneously may provide an additive effect in neurodegenerative diseases.

References:

1.     Klionsky, D. J. and S. D. Emr. Autophagy as a regulated pathway of cellular degradation. Science 290: 1717-1721, 2000.

2.     Carmichael, J. et al. Glycogen synthase kinase-3b inhibitors prevent cellular polyglutamine toxicity caused by the Huntington’s disease mutation. J. Biol. Chem.277: 33791-33798, 2002.