Roles of autophagy in brain homeostasis and disease

Macroautophagy (autophagy) is a lysosome-dependent degradative pathway that encapsulates proteins and organelles within double-membraned vesicles and recycles the contents back into the cell. The interplay of autophagy with various membrane trafficking pathways is crucial for maintaining cellular homeostasis both under basal conditions and in response to environmental stress. In the CNS, neurons and glial cells rely on a spectrum of quality-control and recycling pathways, notably autophagy, to sustain the intricate functions of the brain. Genetic variants in autophagy genes are known to cause Mendelian disorders primarily affecting the human nervous system, underscoring the critical role of autophagy in brain function. We review the latest research delineating the landscape and network of autophagy in developing and mature neurons, elucidating how conserved autophagy pathways regulate neuronal homeostasis and functions at different ages. We examine the increasing evidence of dysfunctional autophagy that contributes to neurodevelopmental disorders, neurodegenerative diseases and psychiatric conditions. Recent insights into the dysregulation of autophagy provide valuable avenues for biomarker identification and therapeutic development, particularly targeting autophagy-lysosome pathways for neurological disorders.