Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies

doi:doi:10.1038/cdd.2008.110

Abstract

The formation of intra-neuronal mutant protein aggregates is a characteristic of several human neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease (PD) and polyglutamine disorders, including Huntington's disease (HD). Autophagy is a major clearance pathway for the removal of mutant huntingtin associated with HD, and many other disease-causing, cytoplasmic, aggregate-prone proteins. Autophagy is negatively regulated by the mammalian target of rapamycin (mTOR) and can be induced in all mammalian cell types by the mTOR inhibitor rapamycin. It can also be induced by a recently described cyclical mTOR-independent pathway, which has multiple drug targets, involving links between Ca²⁺–calpain–G_s and cAMP–Epac–PLC-–IP₃ signalling. Both pathways enhance the clearance of mutant huntingtin fragments and attenuate polyglutamine toxicity in cell and animal models. The protective effects of rapamycin in vivo are autophagy-dependent. In Drosophila models of various diseases, the benefits of rapamycin are lost when the expression of different autophagy genes is reduced, implicating that its effects are not mediated by autophagy-independent processes (like mild translation suppression). Also, the mTOR-independent autophagy enhancers have no effects on mutant protein clearance in autophagy-deficient cells. In this review, we describe various drugs and pathways inducing autophagy, which may be potential therapeutic approaches for HD and related conditions.

Keywords:

autophagy, Huntington's disease, rapamycin

Abbreviations:

AC, adenylyl cyclase; AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; ₂-AR, ₂-adrenergic receptor; cAMP, cyclic AMP; CBZ, carbamazepine; CMA, chaperone-mediated autophagy; DAG, diacylglycerol; 2'5'ddA, 2'5'-dideoxyadenosine; ER, endoplasmic reticulum; FIP200, focal adhesion kinase family interacting protein of 200 kDa; FKBP12, FK506-binding protein 12; GL, G-protein -subunit like protein; GSK-3, glycogen synthase kinase-3; HAP1A, huntingtin-associated protein-1A; HD, Huntington's disease; hsc70, heat shock cognate protein of 70 kDa; IMPase, inositol monophosphatase; Ins, inositol; IP₃, inositol 1,4,5-trisphosphate; IP₄, inositol 1,3,4,5-tetrakisphosphate; IP₃R, IP₃ receptor; I1R, inidazoline-1 receptor; LAMP2A, lysosome-associated membrane protein type 2A; 3-MA, 3-methyladenine; MAP1-LC3, microtubule-associated protein 1 light chain 3; MEF, mouse embryonic fibroblast; mGluR1/5, class 1 metabotropic glutamate receptor; mhtt, mutant huntingtin; mTOR, mammalian target of rapamycin; NMDAR, N-methyl-D-aspartate receptors; PACAP, pituitary adenylyl cyclase-activating polypeptide; PAS, phagophore assembly site; PD, Parkinson's disease; PI3K, phosphatidylinositol 3-kinase; PIP₂,phosphatidylinositol 4,5-bisphosphate|PKA, protein kinase A; PLC, phospholipase C; polyA, polyalanine; polyQ, polyglutamine; raptor, regulatory associated protein of mTOR; SBMA, spinobulbar muscular atrophy; SCA, spinocerebellar ataxias; SMER, small-molecule enhancer of rapamycin; SMIR, small-molecule inhibitor of rapamycin; SOD1, superoxide dismutase 1; TSC, tuberous sclerosis complex; ULK, UNC (uncoordinated movement)-51-like kinase; VPA, valproic acid

Review