Autophagy in Neuronal Development and Plasticity

Growing evidence suggests that autophagy is essential for both developmental and adult neural stem cell maintenance, proliferation, and differentiation. In the mature CNS, autophagy plays a role in plasticity through actions within the axon, dendritic spine, and during synaptic assembly. Defects in autophagy and its role in neurogenesis and neuronal plasticity may contribute to developmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder, memory deficits, and psychiatric disorders such as depression. Autophagy is a highly conserved intracellular clearance pathway in which cytoplasmic contents are trafficked to the lysosome for degradation. Within neurons, it helps to remove damaged organelles and misfolded or aggregated proteins and has therefore been the subject of intense research in relation to neurodegenerative disease. However, far less is understood about the role of autophagy in other aspects of neuronal physiology. Here we review the literature on the role of autophagy in maintaining neuronal stem cells and in neuronal plasticity in adult life and we discuss how these contribute to structural and functional deficits observed in a range of human disorders. Autophagy is a highly conserved intracellular clearance pathway in which cytoplasmic contents are trafficked to the lysosome for degradation. Within neurons, it helps to remove damaged organelles and misfolded or aggregated proteins and has therefore been the subject of intense research in relation to neurodegenerative disease. However, far less is understood about the role of autophagy in other aspects of neuronal physiology. Here we review the literature on the role of autophagy in maintaining neuronal stem cells and in neuronal plasticity in adult life and we discuss how these contribute to structural and functional deficits observed in a range of human disorders. AMPK phosphorylates and therefore regulates multiple components of the autophagy initiation pathway. It inhibits MTORC1 and activates ULK1. proteins encoded by the autophagy-related (ATG) gene family. protein complexes involved in membrane remodelling during phagophore closure. When ESCRT machinery is disrupted, unclosed autophagosomes accumulate. a transmembrane protein found on lysosomes. macrocephaly is clinically described as an abnormally enlarged head. It may be caused by an enlarged brain or by accumulation of cerebrospinal fluid (hydrocephalus). a disorder where the brain fails to develop properly and can be identified by reduced head size. This may be evident at birth or within early childhood. the selective degradation of mitochondria by autophagy machinery. mammalian (or mechanistic) target of rapamycin (mTOR) is a serine/threonine protein kinase that is a component of two different protein complexes, MTORC1 and MTORC2. In addition to regulating autophagy, MTORC1 regulates transcription and protein synthesis. MTORC2 is involved in the maintenance of the actin cytoskeleton and also activates insulin and insulin-like growth factor receptors. Rapamycin is a naturally occurring bacterial macrolide that inhibits MTOR and is commonly used experimentally to upregulate autophagy. SNAp REceptor proteins are complexes involved in vesicle fusion. a kinase that phosphorylates several proteins required for the initiation of autophagy. ULK1 phosphorylates itself and can also be inhibited by MTORC1, which reduces its activity.