Recent progress in the role of autophagy in neurological diseases

Abstract

Autophagy (here refers to macroautophagy) is a catabolic pathway by which large protein aggregates and damaged organelles are first sequestered into a double-membraned structure called autophago-some and then delivered to lysosome for destruction. Recently, tremen-dous progress has been made to elucidate the molecular mechanism and functions of this essential cellular metabolic process. In addition to being either a rubbish clearing system or a cellular surviving program in response to different stresses, autophagy plays important roles in a large number of pathophysiological conditions, such as cancer, diabetes, and especially neurodegenerative disorders. Here we review recent progress in the role of autophagy in neurological diseases and discuss how dysregulation of autophagy initiation, autophagosome formation, maturation, and/or au-tophagosome-lysosomal fusion step contributes to the pathogenesis of these disorders in the nervous system.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Huntington's disease; Parkinson's disease; autophagy; mTOR; neuro-degenerative diseases.

Figure 1. FIGURE 1: Schematic of the mammalian autophagy pathway.

This diagram shows a simplified version of autophagy. Nutrient or growth factor deprivation and low energy are well established autophagy inducers, leading to AMPK activation and mTORC1 inhibition, which positively trigger the formation of ULK1 complex (ULK1, ULK2, ATG13, FIP200 and ATG101). This complex subsequently activates the VSP34 complex (VSP34, Beclin1, VSP15 and ATG14) to promote PI3P synthesis in pre-autophagosomal structures, thus the initiation of autophagy has been activated. PI3P specifically binds its effector WIPI2 and catalyzes two types of ubiquitination-like reactions that are in charge of the extension and closure of the autophagosome double membranes. In the first reaction, ATG12 and ATG5 are conjugated to each other in the presence of ATG7 and ATG10, and ATG16L subsequently binds to them to form the ATG12–ATG5–ATG16L1 complex. In the second reaction, LC3-I and PE are conjugated to membranes in the presence of ATG14, ATG7 and ATG3, this process is facilitated by the ATG12–ATG5–ATG16L1 complex, ultimately leading to the formation of the complete autophagosome. Receptor proteins such as p62, NDP52, and NBR1 are responsible for the recognition of cytoplasmic targets (e.g., protein aggregates, damaged mitochondria, ER/ribosome, and infectious agents), and establish a bridge between LC3-II and specific ubiquitinated cargos to sustain the engulfment of a variety of substrates. In the final step of the process, the completed autophagosomes are then trafficked to fuse with lysosomes, resulting in the degradation of the vesicle contents, and this process is regulated by LAMP1/2, EPG5, HOPS, PLEKHM1 and SNAREs. AMPK - AMP-activated protein kinase; mTORC1 - mechanistic target of rapamycin complex 1; ULK1 - Unc-51-like kinase; ATG - autophagy protein; VPS34 - phosphatidylinositol 3-kinase VPS34; PI3P - phosphatidylinositol 3-phosphate; PE - phosphatidylethanolamine; RP - receptor protein.

Figure 2. FIGURE 2: An overview of the autophagy pathway and the site of action of disease-associated proteins.

A huge number of neurodegenerative disease-related genes have been implicated in autophagy function. Mutation or deletion of these genes have been suggested to be involved in perturbation throughout the autophagic process, from initiation of autophagosome formation to degradation in the autolysosomes. Their proposed sites of action are highlighted in boxes. Please note that some disease-associated proteins act at multiple points in the process. AD - Alzheimer disease; PD - Parkinson's disease; HD - Huntington's disease; ALS - amyotrophic lateral sclerosis.