Control of autophagy as a therapy for neurodegenerative disease

Autophagy is an intracellular degradation process that clears long-lived proteins and organelles from the cytoplasm. It involves the formation of double-membraned structures called autophagosomes that can engulf portions of cytoplasm containing oligomeric protein complexes and organelles, such as mitochondria. Autophagosomes fuse with lysosomes and their contents then are degraded. Failure of autophagy in neurons can result in the accumulation of aggregate-prone proteins and neurodegeneration. Pharmacological induction of autophagy can enhance the clearance of intracytoplasmic aggregate-prone proteins, such as mutant forms of huntingtin, and ameliorate pathology in cell and animal models of neurodegenerative diseases. In this Review, the autophagic machinery and the signaling pathways that regulate the induction of autophagy are described. The ways in which dysfunctions at multiple stages in the autophagic pathways contribute to numerous neurological disorders are highlighted through the use of examples of Mendelian and complex conditions, including Alzheimer disease, Parkinson disease and forms of motor neuron disease. The different ways in which autophagic pathways might be manipulated for the therapeutic benefit of patients with neurodegenerative disorders are also considered.