Sarkar, S. et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101-1111

Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2XY, England, UK.
The Journal of Cell Biology (Impact Factor: 9.83). 10/2005; 170(7):1101-11. DOI: 10.1083/jcb.200504035
Source: PubMed


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 3beta 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.

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    • "Trehalose and rapamycin would have additive effects in reducing EGFP-HDQ74 aggregates and cell death in COS-7 cells, compared to the single treatment of trehalose or rapamycin [13]. Lithium and rapamycin together facilitated enhanced clearance of soluble EGFP-HDQ74 and A53T a-synuclein, compared to either treatment alone [14]. Although the earlier literature demonstrate that these chemical autophagy inducers may be useful for the therapy of different neurodegenerative diseases, but they are associated with several limitations such as inefficiency at late stage diagnosis of diseases, unwanted side effects etc. [17] [18] which compel us to verify the possibility of combination therapy by other kinds of autophagic inducers to further increase autophagic activity and reduce unwanted side effects to combat against various neurodegenerative diseases. "
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    ABSTRACT: Accelerating the clearance of intracellular protein aggregates through elevation of autophagy represents a viable approach for the treatment of neurodegenerative diseases. In our earlier report, we have demonstrated the enhanced degradation of mutant huntingtin protein aggregates through autophagy process induced by europium hydroxide nanorods [EHNs: Eu(III)(OH)3], but the underlying molecular mechanism of EHNs mediated autophagy was unclear. The present report reveals that EHNs induced autophagy does not follow the classical AKT-mTOR and AMPK signaling pathways. The inhibition of ERK1/2 phosphorylation using the specific MEK inhibitor U0126 partially abrogates the autophagy as well as the clearance of mutant huntingtin protein aggregates mediated by EHNs suggesting that nanorods stimulate the activation of MEK/ERK1/2 signaling pathway during autophagy process. In contrast, another mTOR-independent autophagy inducer trehalose has been found to induce autophagy without activating ERK1/2 signaling pathway. Interestingly, the combined treatment of EHNs and trehalose leads to more degradation of mutant huntingtin protein aggregates than that obtained with single treatment of either nanorods or trehalose. Our results demonstrate the rational that further enhanced clearance of intracellular protein aggregates, needed for diverse neurodegenerative diseases, may be achieved through the combined treatment of two or more autophagy inducers, which stimulate autophagy through different signaling pathways.
    Full-text · Article · Sep 2015 · Biomaterials
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    • "A primordial signaling pathway regulating autophagy, which is conserved from yeast to humans, is mediated by the mammalian target of rapamycin complex 1 (mTORC1), which inhibits autophagy by phosphorylating proteins such as ATG1 and ATG13 that act upstream in phagophore formation (Hosokawa et al., 2009; Jung et al., 2009). However, several mTORC1-independent pathways have been described, including low inositol triphosphate levels (Sarkar et al., 2005), which activate autophagy by activating AMP-activated protein kinase (AMPK). Low inositol triphosphate levels reduce "
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    ABSTRACT: Autophagy is a conserved process that uses double-membrane vesicles to deliver cytoplasmic contents to lysosomes for degradation. Although autophagy may impact many facets of human biology and disease, in this review we focus on the ability of autophagy to protect against certain neurodegenerative and infectious diseases. Autophagy enhances the clearance of toxic, cytoplasmic, aggregate-prone proteins and infectious agents. The beneficial roles of autophagy can now be extended to supporting cell survival and regulating inflammation. Autophagic control of inflammation is one area where autophagy may have similar benefits for both infectious and neurodegenerative diseases beyond direct removal of the pathogenic agents. Preclinical data supporting the potential therapeutic utility of autophagy modulation in such conditions is accumulating. © 2015 Rubinsztein et al.
    Full-text · Article · Jun 2015 · Journal of Experimental Medicine
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    • "Lithium, carbamazepine and sodium valproate are currently approved drugs used to treat mood disorders and epilepsy. They target d-myo-inositol-1,4,5-triphosphate (IP3)-regulated pathway, depleting intracellular inositol, and therefore induce autophagy (Sarkar et al. 2005; Rubinsztein et al. 2007). Tamoxifen is a drug currently used to treat a wide variety of diseases, from breast cancer to mood disorders and infertility, among others. "
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    ABSTRACT: Tuberculosis (TB), a chronic infectious disease mainly caused by the tubercle bacillus Mycobacterium tuberculosis, is one of the world's deadliest diseases that has afflicted humanity since ancient times. Although the number of people falling ill with TB each year is declining, its incidence in many developing countries is still a major cause of concern. Upon invading host cells by phagocytosis, M. tuberculosis can replicate within infected cells by arresting the maturation of the phagosome whose function is to target the pathogen for elimination. Host cells have mechanisms of controlling this evasion by inducing autophagy, an elaborate cellular process that targets bacteria for progressive elimination, decreasing bacterial loads within infected cells. In addition, autophagy activation also aids in the control of inflammation, contributing to a more efficient innate immune response against M. tuberculosis. Several innovative TB therapies have been envisaged based on autophagy manipulation, with some of them revealing high potential for future clinical trials and eventual implementation in healthcare systems. Thus, this review highlights the recent advances on the innate immune response regulation by autophagy upon M. tuberculosis infection and the promising new autophagy-based therapies for TB.
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