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Autophagy in the mammalian nervous system: a primer for neuroscientists.

ABSTRACT: Autophagy refers to the lysosomal degradation of damaged or superfluous components and is essential for metabolic plasticity and tissue integrity. This evolutionarily conserved process is particularly vital to mammalian post-mitotic cells such as neurons, which face unique logistical challenges and must sustain homoeostasis over decades. Defective autophagy has pathophysiological importance, especially for human neurodegeneration. The present-day definition of autophagy broadly encompasses two distinct yet related phenomena: non-selective and selective autophagy. In this minireview, we focus on established and emerging concepts in the field, paying particular attention to the physiological significance of macroautophagy and the burgeoning world of selective autophagy pathways in the context of the vertebrate nervous system. By highlighting established basics and recent breakthroughs, we aim to provide a useful conceptual framework for neuroscientists interested in autophagy, in addition to autophagy enthusiasts with an eye on the nervous system.

SUBMITTER: Suomi F

PROVIDER: S-EPMC7104325 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Autophagy in the mammalian nervous system: a primer for neuroscientists.

Suomi Fumi F McWilliams Thomas G TG

Neuronal signaling 20190911 3

Autophagy refers to the lysosomal degradation of damaged or superfluous components and is essential for metabolic plasticity and tissue integrity. This evolutionarily conserved process is particularly vital to mammalian post-mitotic cells such as neurons, which face unique logistical challenges and must sustain homoeostasis over decades. Defective autophagy has pathophysiological importance, especially for human neurodegeneration. The present-day definition of autophagy broadly encompasses two d ...[more]

PMID: 32269837

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Project description:Dendritic arborizations of many neurons are patterned by a process called self-avoidance, in which branches arising from a single neuron repel each other. By minimizing gaps and overlaps within the arborization, self-avoidance facilitates complete coverage of a neuron’s territory by its neurites. Remarkably, some neurons that display self-avoidance interact freely with other neurons of the same subtype, implying that they discriminate self from non-self. Here we demonstrate roles for the clustered protocadherins (Pcdhs) in dendritic self-avoidance and self/non-self discrimination. The Pcdh locus encodes 58 related cadherin-like transmembrane proteins, at least some of which exhibit isoform-specific homophilic adhesion in heterologous cells and are expressed stochastically and combinatorially in single neurons. Deletion of all 22 Pcdh genes in the mouse γ-subcluster (Pcdhg genes) disrupts self-avoidance of dendrites in retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells. Further genetic analysis of SACs showed that Pcdhg proteins act cell-autonomously during development, and that replacement of the 22 Pcdhg proteins with a single isoform restores self-avoidance. Moreover, expression of the same single isoform in all SACs decreases interactions among dendrites of neighbouring SACs (heteroneuronal interactions). These results suggest that homophilic Pcdhg interactions between sibling neurites (isoneuronal interactions) generate a repulsive signal that leads to self-avoidance. In this model, heteroneuronal interactions are normally permitted because dendrites seldom encounter a matched set of Pcdhg proteins unless they emanate from the same soma. In many respects, our results mirror those reported for Dscam1 (Down syndrome cell adhesion molecule) in Drosophila: this complex gene encodes thousands of recognition molecules that exhibit stochastic expression and isoform-specific interactions, and mediate both self-avoidance and self/non-self discrimination. Thus, although insect Dscam and vertebrate Pcdh proteins share no sequence homology, they seem to underlie similar strategies for endowing neurons with distinct molecular identities and patterning their arborizations.

Dataset Information

Autophagy in the mammalian nervous system: a primer for neuroscientists.

Publications

Autophagy in the mammalian nervous system: a primer for neuroscientists.

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