Autophagy in mammalian neurodevelopment and implications for childhood neurological disorders

Here we explore the neurodevelopmental aspects of macroautophagy (henceforth known as autophagy), the process by which cells remove and remodel their structure in a regulated and spatially restricted manner. Autophagy is a catabolic pathway in which cytosolic substances, such as protein complexes, lipids, and organelles, are engulfed by an autophagic vesicle. Degradation occurs once an autophagosome fuses with a lysosome, allowing the macromolecular cargo sequestered within the autophagic vesicle to be recycled. It is firmly established that autophagy plays a pivotal role in maintaining cellular homeostasis. Nevertheless, new evidence has emerged that the molecular mechanisms which regulate brain growth and neuronal connectivity involve autophagic processes. Our aim, as we endeavor to review data from model systems, is to show that autophagy performs a fundamental role in the development of the central nervous system (CNS). Moreover, we discuss human genetic data to underscore that mutations in autophagy-related genes are a contributing factor in childhood neurological disorders. To emphasize the importance of regulated vesicle transport pathways during the formation of the CNS, we discuss autophagy in relation to endosomal sorting to the lysosome, and explore how these mechanisms might intersect to regulate developmental events. We maintain that a deeper understanding of the function of autophagy in the CNS can shed new light on the biological basis of neurodevelopmental disorders.