Regulation of neuronal autophagy and the implications in neurodegenerative diseases

Abstract

Neurons are highly polarized and post-mitotic cells with the specific requirements of neurotransmission accompanied by high metabolic demands that create a unique challenge for the maintenance of cellular homeostasis. Thus, neurons rely heavily on autophagy that constitutes a key quality control system by which dysfunctional cytoplasmic components, protein aggregates, and damaged organelles are sequestered within autophagosomes and then delivered to the lysosome for degradation. While mature lysosomes are predominantly located in the soma of neurons, the robust, constitutive biogenesis of autophagosomes occurs in the synaptic terminal via a conserved pathway that is required to maintain synaptic integrity and function. Following formation, autophagosomes fuse with late endosomes and then are rapidly and efficiently transported by the microtubule-based cytoplasmic dynein motor along the axon toward the soma for lysosomal clearance. In this review, we highlight the recent knowledge of the roles of autophagy in neuronal health and disease. We summarize the available evidence about the normal functions of autophagy as a protective factor against neurodegeneration and discuss the mechanism underlying neuronal autophagy regulation. Finally, we describe how autophagy function is affected in major neurodegenerative diseases with a special focus on Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis.

Keywords: Alzheimer's disease; Amphisome; Amyotrophic lateral sclerosis; Autophagosome; Autophagy; Axonal transport; Lysosome; Mitophagy; Parkinson's disease; Synaptic autophagy.