Core autophagy genes and human diseases

Autophagy involves the formation of double-membrane autophagosomes and their delivery to lysosomes for degradation. In response to various endogenous and exogenous stimuli, autophagy recycles cellular constituents and removes cytotoxic threats such as protein aggregates and damaged organelles to maintain cellular homeostasis. Dysfunctional autophagy has been linked with multiple human diseases, including neurodegenerative diseases, tumorigenesis, diabetes, and immune diseases. Here we focus on human genetic disorders caused by hypomorphic or regulatory mutations in early acting autophagy genes or by mutations in genes acting at autophagosome maturation. Protein aggregates assembled via liquid-liquid phase separation (LLPS) exhibit distinct biophysical properties that are modulated by disease-related mutations. Abnormal phase transition of protein aggregates affects their removal and is associated with the pathogenesis of various neurodegenerative diseases.