Roles of autophagy in brain homeostasis and disease

Henry Kim and colleagues review autophagy in developing and mature neurons and glial cells. They describe macroautophagy as a lysosome-dependent recycling system that removes proteins and organelles and returns their components to the cell. Genetic variants in autophagy genes cause human Mendelian disorders that primarily affect the nervous system. The review connects altered autophagy-lysosome activity with neurodevelopmental disorders, neurodegeneration, and psychiatric conditions. It also discusses age-dependent changes in neuronal quality control and the interaction of autophagy with membrane-trafficking pathways. The translational focus is biomarker discovery and therapeutic targeting of autophagy-lysosome pathways. This is not a clinical trial and it does not establish that fasting, rapamycin, spermidine, or another autophagy-modulating intervention improves human longevity. Its value is mechanistic: it organizes evidence linking cellular recycling to brain maintenance and identifies intervention points that require clinical testing.

Recent insights into the dysregulation of autophagy provide valuable avenues for biomarker identification and therapeutic development, particularly targeting autophagy-lysosome pathways for neurological disorders.