Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway

By A. Williams, Sovan Sarkar, P. Cuddon, Evangelia K Ttofi, S. Saiki, Farah H. Siddiqi, Luca Jahreiss, Angeleen Fleming, Dean C. Pask, P. Goldsmith and 3 more. Nature Chemical Biology, 2008

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Autophagy is a major clearance route for intracellular aggregate-prone proteins causing diseases like Huntington’s disease. Autophagy induction with the mTOR inhibitor, rapamycin, accelerates clearance of these toxic substrates. As rapamycin has non-trivial side effects, we screened FDA-approved drugs to identify novel autophagy-inducing pathways. We found that L-type Ca2+ channel antagonists, the K+ATP channel opener minoxidil, and the Gi signaling activator clonidine, induce autophagy. These drugs revealed a cyclical mTOR-independent pathway regulating autophagy, where cAMP regulates IP3 levels, influencing calpain activity, which completes the cycle by cleaving and activating Gsα, which regulates cAMP levels. This pathway has numerous potential points where autophagy can be induced and we provide proof-of-principle for therapeutic relevance in Huntington’s disease using mammalian cell, fly and zebrafish models. Our data also suggest that insults that elevate intracytosolic Ca2+, like excitotoxicity, will inhibit autophagy, thus retarding clearance of aggregate-prone proteins.

Subfields: Cell Biology, Cellular and Molecular Neuroscience, Epidemiology

View Paper: https://www.semanticscholar.org/paper/5a99be2793d18b3c21dbccb5bb171f50cf0f982d

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Citations in the corpus

Autophagy and aging. (2011, background): “IP3 may regulate autophagy negatively by binding to ER IP3 receptors, which releases Ca 2+ from stores in the ER, resulting in the activation of proteases of the calpain family that inhibit autophagy by cleaving and activating Gsa, which produces excess cAMP (Williams et al., 2008).”
Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, positive): “Finally, a growing number of autophagy inducers are being characterized which may act on other pathways, including compounds acting on the modulation of cAMP/IP3, such as rilmenidine, clonidine, minoxidil and verapamil, which have been shown to ameliorate phenotypes in animal models of HD (Rose et a”
Guidelines for the use and interpretation of assays for monitoring autophagy (2012, background): “Along these lines, glucose depletion may be much more efficient at inducing autophagy than rapamycin or amino acid starvation in neurons in culture (Germain M, Slack R, personal communication); although a number of compounds can also be quite efficient autophagy inducers in neurons including the cal”
The Role of Autophagy in Cancer: Therapeutic Implications (2011, background): “In studies using cell-based screening assays, the antihypertensive drugs verapamil, minoxidil, and clonidine were found to induce autophagy through an mTOR-independent pathway involving calpain (65).”
Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein (2017, background): “…2004; Greiner and Yang, 2011; Bhat et al., 2014; Pavese et al., 2006), microglia activation (Gusella and MacDonald, 2009), a systematic exploration of coding (Gusella and MacDonald, 2009) and non-coding (Zhang and Friedlander, 2011) DNA, and autophagy (Sarkar et al., 2009; Williams et al., 2008).”
PI(5)P Regulates Autophagosome Biogenesis (2015, background): “, 1999), like other autophagy inducers (Williams et al., 2008), while PI5P4K2C overexpression had the opposite effect (Figures 4C–4E).”
Autophagy and the integrated stress response (2010, neutral): “Indeed, stimulation of the general autophagic pathway, either by inhibiting mTOR or by stimulating mTORindependent autophagy pathways, leads to reduced accumulation of mutated, aggregationprone proteins (such as mutant α-synyclein- or huntingtin protein) and damaged mitochondria (Sarkar et al., 2007”
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Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. (2010, background): “Constitutive InsP3R Ca 2+ Release Is Required to Inhibit Prosurvival Autophagy in Normal Conditions The InsP3R has been implicated in mTOR-independent autophagy (Criollo et al., 2007; Sarkar et al., 2005; Vicencio et al., 2009; Williams et al., 2008).”