Autophagy and Neurodegenerative Diseases

Autophagy is a highly regulated cellular mechanism that results in the bulk degradation of long-lived proteins and organelles and which seems to be implicated in a variety of physiological and pathological conditions relevant to neurological diseases. The formation of intraneuronal mutant protein aggregates is a characteristic of several human neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, and polyglutamine disorders such as Huntington’s disease (HD). Autophagy is a major clearance pathway for the removal of the mutant huntingtin protein 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 an mTOR-independent pathway, which has multiple drug targets, involving links between Ca2+-calpain–Gsα and cAMP–Epac–PLC-e–IP3 signaling. Both pathways enhance the process of autophagy. In this review, we describe the various drugs and pathways that induce autophagy that are potentia