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Review
. 2012 May;97(2):67-82.
doi: 10.1016/j.pneurobio.2011.08.013. Epub 2011 Sep 10.

Autophagy and polyglutamine diseases

Maria Jimenez-Sanchez  1 , Frances Thomson, Eszter Zavodszky, David C Rubinsztein
Affiliations
Review

Autophagy and polyglutamine diseases

Maria Jimenez-Sanchez et al. Prog Neurobiol. 2012 May.

Abstract

In polyglutamine diseases, an abnormally elongated polyglutamine tract results in protein misfolding and accumulation of intracellular aggregates. The length of the polyglutamine expansion correlates with the tendency of the mutant protein to aggregate, as well as with neuronal toxicity and earlier disease onset. Although currently there is no effective cure to prevent or slow down the progression of these neurodegenerative disorders, increasing the clearance of mutant proteins has been proposed as a potential therapeutic approach. The ubiquitin-proteasome system and autophagy are the two main degradative pathways responsible for eliminating misfolded and unnecessary proteins in the cell. We will review some of the studies that have proposed autophagy as a strategy to reduce the accumulation of polyglutamine-expanded protein aggregates and protect against mutant protein neurotoxicity. We will also discuss some of the currently known mechanisms that induce autophagy, which may be beneficial for the treatment of these and other neurodegenerative disorders.

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Figures

Fig. 1
Fig. 1
Autophagy machinery. Autophagy is a bulk degradation process in which portions of cytoplasm are engulfed by autophagosomes and degraded by fusion with lysosomes. Current evidence suggests that multiple compartments, including the endoplasmic reticulum, Golgi, mitochondria, and the plasma membrane may act as lipid donors to the growing phagophore, and Atg9 has been implicated in the membrane delivery. The Beclin 1 complex regulates the formation of autophagosomes, and includes autophagy-related proteins (shown in dark blue), and proteins that inhibit autophagy (shown in light blue). An important component of the complex is Vps34, a class III phosphatidylinositol 3-kinase responsible for the formation of phosphatidylinositol-3-phosphate, which is thought to recruit autophagy-specific proteins. The anti-apoptotic protein Bcl-2 inhibits autophagy, but is itself inhibited by phosphorylation mediated by JNK1 under starvation conditions. Two ubiquitin-like reactions contribute to the elongation of phagophores. In the first, Atg12 is conjugated to Atg5 via the concerted actions of Atg7 and Atg10 (E1-like and E2-like, respectively), and the resulting conjugate associates with Atg16L. This complex is found on the outer leaf of phagophores, and dissociates from completed autophagosomes. In the second ubiquitin-like reaction, LC3 is first trimmed by Atg4B to form LC3-I, and is subsequently conjugated to phosphatidylethanolamine by Atg7 and Atg3 to form LC3-II. LC3-II is found on the inner and outer membranes of phagophores and autophagosomes, and is recycled from the outer membrane of mature autolysosomes by Atg4B.
Fig. 2
Fig. 2
Inducing autophagy by inhibiting the mTOR pathway. mTOR is a downstream effector of the class I phosphoinositol 3-kinase (PI3K) pathway. The PI3K pathway regulates AKT phosphorylation which, in turn, inhibits the tuberous sclerosis complex (TSC)1/2, which activates the small GTPase Rheb, resulting in mTORC1 activation. Rapamycin interacts with FKBP12 which binds to and inhibits mTORC1. Inhibition of mTORC1 by rapamycin results in dephosphorylation-dependent activation of ULK1 and subsequent ULK1-mediated phosphorylation of Atg13, FIP200 and ULK1 itself, inducing autophagosome synthesis. The rapamycin analogue CCI-779, glucose, glucose-6-phosphate, Torin1, perhexiline, niclosamide and rottlerin also inhibit mTORC1 activity, either directly or indirectly. Dexamethasone induces autophagy via Akt inhibition. PI103 and structurally related compounds induce autophagy by inhibiting both PI3K and mTOR. Phenethyl isothiocyanate (PEITC) induces autophagy partially by suppressing the phosphorylation of Akt and mTOR. The vitamin E antioxidant activates the mTOR pathway and inhibits autophagy.
Fig. 3
Fig. 3
Inducing autophagy independent of the mTOR pathway. The cyclical mTOR-independent pathway consists of the cAMP-Epac-PLC-ɛ, phosphoinositol and Ca2+-calpain-GSα pathways and has multiple points where it can be modulated to induce autophagy in order to treat polyglutamine diseases. Intracellular cAMP levels are increased by adenylyl cyclase (AC), which activates Epac, which in turn activates the small G-protein Rap2B that activates phospholipase C (PLC)-ɛ. PLC-ɛ activation results in the production of IP3 from phosphatidylinositol 4,5-bisphosphate (PIP2) and IP3 binds to the endoplasmic reticulum (ER) IP3Rs releasing Ca2+ from ER Ca2+ stores. Intracytosolic Ca2+ levels are also increased by Ca2+ influx due to L-type Ca2+ channel agonist binding. Increase in intracytosolic Ca2+ activates the cysteine protease calpains which cleave and activate GSα. GSα activation results in an increase in AC activity elevating cAMP levels, therefore as part of a loop. Activation of this loop pathway inhibits autophagy. Drugs targeting targets at different stages within the loop can induce autophagy and are protective in various polyglutamine disease models such as: imidazoline-1-receptor (I1R) agonists (clonidine and rilmenidine) and the AC inhibitor 2′,5′-dideoxyadenosine (2′5′ddA) that act to decrease cAMP levels; agents that reduce inositol and IP3 levels (lithium, L-690,330, sodium valproate and carbamazepine); Ca2+ channel blockers (verapamil, loperamide, amiodarone, nimodipine, nitrendipine, niguldipine and pimozide); calpain inhibitors (calpastatin and calpeptin) and the GSα inhibitor NF449. JNK phosphorylation of Bcl-2 results in the dissociation of Bcl-2 from Beclin 1 causing an induction of autophagy. The thiol antioxidants N-acetyl cysteine (NAC) and glutathione inhibit JNK activation and thus inhibit the phosphorylation of Bcl-2 resulting in the inhibition of autophagy as shown in cell, fly and zebrafish models of HD.
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