Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications

Abstract

Autophagy is a highly conserved intracellular pathway involved in the elimination of proteins and organelles by lysosomes. Known originally as an adaptive response to nutrient deprivation in mitotic cells, autophagy is now recognized as an arbiter of neuronal survival and death decisions in neurodegenerative diseases. Studies using postmortem human tissue, genetic and toxin-induced animal and cellular models indicate that many of the etiological factors associated with neurodegenerative disorders can perturb the autophagy process. Emerging data support the view that dysregulation of autophagy might play a critical role in the pathogenesis of neurodegenerative disorders. In this review, we highlight the pathophysiological roles of autophagy and its potential therapeutic implications in debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis and Alzheimer's, Parkinson's and Huntington's diseases.

Figure 1. Steps involved in the autophagic process and their role in common neurodegenerative disorders

The autophagic process involves- 1) Formation of pre-autophagosomal structures- a membrane source provides lipid bilayers for formation of a phagophore by a process known as “nucleation”. 2) Phagophore/Isolation membrane formation - here a double membranous phagophore or isolation membrane derived from pre-autophagosomal structures sequester portions of cytosol, including organelles that leads to 3) the formation of autophagosomes. 4) Maturation phase- the completed autophagosomes during this step undergo maturation, which involves steps such as fusion with multivesicular bodies or endosomes to form an amphisome. 5) Docking and fusion- during this step the inner membrane compartment fuses with a lysosome and its contents are degraded by lysosomal hydrolases. The three major forms of autophagy prevalent amongst common neurodegenerative disorders are macroautophagy, microautophagy and chaperone-mediated autophagy (see text for the detailed description of the three types of autophagy and how they are associated with pathogenesis of common neurodegenerative disorders).