Autophagy modulation as a potential therapeutic target for diverse diseases

Abstract

Autophagy is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles. It begins when double-membraned autophagosomes engulf portions of cytoplasm, which is followed by the fusion of these vesicles with lysosomes and degradation of the autophagic contents. In addition to its vital homeostatic role, this degradation pathway is involved in various human disorders. This Review provides an overview of the mechanisms involved in autophagy, and briefly reviews the various signalling pathways that control the process, as a backdrop for considering potential targets that may be druggable. We consider the roles of autophagy in different diseases, focusing on metabolic diseases, neurodegenerative diseases, cancers, infectious diseases and immunity. Autophagy may be inhibited or activated during different diseases, and the possible consequences of these effects are explored. We discuss disease states in which autophagy upregulation or inhibition may be beneficial. Candidate therapeutic possibilities for autophagy inhibition, autophagy upregulation and modulation of the clearance of selective autophagy substrates are also considered, and we provide an overview of the different pharmacological agents that are currently available as potential drugs and chemical probes. Last, we consider some possible future directions as well as caveats for various therapeutic approaches involving autophagy modulation.