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

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 Ca 2 þ -calpain-G sa and cAMPEpac-PLC-e-IP 3 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 mTORindependent 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.

Proteostasis impairment in protein-misfolding and -aggregation diseases

“…Increasing proteolytic capacity provides an alternative approach to maintaining proteostasis. This may be achieved by induction of autophagy [95] or by inhibiting specific deubiquitinating enzymes, thereby increasing the rate at which the UPS clears misfolded proteins [96].…”

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

“…Autophagy has previously been shown to have an important role in the clearance of protein with polyQ stretches 28 . To exclude that unbalanced autophageal degradation causes the seen effect, the above-mentioned experiments were repeated in autophagy negative mouse embryonic fibroblasts, which were derived from mice deficient for Atg5 (Atg À / À ) 29 .…”

GSK-3β : une kinase au cœur des maladies neuro-dégénératives ?

“…De plus, le lithium réduirait la quantité des agrégats protéiques intracellulaires. Combiné à la rapamycine, un activateur d'autophagie favorisant la dégradation des agrégats protéiques, le lithium présenterait un fort potentiel thérapeutique dans la MH [35].…”