RRC ID 37017
Author Maday S, Holzbaur EL.
Title Compartment-Specific Regulation of Autophagy in Primary Neurons.
Journal J Neurosci
Abstract UNLABELLED:Autophagy is an essential degradative pathway that maintains neuronal homeostasis and prevents axon degeneration. Initial observations suggest that autophagy is spatially regulated in neurons, but how autophagy is regulated in distinct neuronal compartments is unclear. Using live-cell imaging in mouse hippocampal neurons, we establish the compartment-specific mechanisms of constitutive autophagy under basal conditions, as well as in response to stress induced by nutrient deprivation. We find that at steady state, the cell soma contains populations of autophagosomes derived from distinct neuronal compartments and defined by differences in maturation state and dynamics. Axonal autophagosomes enter the soma and remain confined within the somatodendritic domain. This compartmentalization likely facilitates cargo degradation by enabling fusion with proteolytically active lysosomes enriched in the soma. In contrast, autophagosomes generated within the soma are less mobile and tend to cluster. Surprisingly, starvation did not induce autophagy in either the axonal or somatodendritic compartment. While starvation robustly decreased mTORC1 signaling in neurons, this decrease was not sufficient to activate autophagy. Furthermore, pharmacological inhibition of mammalian target of rapamycin with Torin1 also was not sufficient to markedly upregulate neuronal autophagy. These observations suggest that the primary physiological function of autophagy in neurons may not be to mobilize amino acids and other biosynthetic building blocks in response to starvation, in contrast to findings in other cell types. Rather, constitutive autophagy in neurons may function to maintain cellular homeostasis by balancing synthesis and degradation, especially within distal axonal processes far removed from the soma.
SIGNIFICANCE STATEMENT:Autophagy is an essential homeostatic process in neurons, but neuron-specific mechanisms are poorly understood. Here, we compare autophagosome dynamics within neuronal compartments. Axonal autophagy is a vectorial process that delivers cargo from the distal axon to the soma. The soma, however, contains autophagosomes at different maturation states, including input received from the axon combined with locally generated autophagosomes. Once in the soma, autophagosomes are confined to the somatodendritic domain, facilitating cargo degradation and recycling of biosynthetic building blocks to primary sites of protein synthesis. Neuronal autophagy is not robustly upregulated in response to starvation or mammalian target of rapamycin inhibition, suggesting that constitutive autophagy in neurons maintains homeostasis by playing an integral role in regulating the quality of the neuronal proteome.
Volume 36(22)
Pages 5933-45
Published 2016-6-1
DOI 10.1523/JNEUROSCI.4401-15.2016
PII 36/22/5933
PMID 27251616
PMC PMC4887563
MeSH Amino Acids / deficiency Animals Autophagy / drug effects Autophagy / physiology* Axons / drug effects Axons / physiology Biological Transport / drug effects Biological Transport / physiology Cells, Cultured Dendrites / drug effects Dendrites / physiology Embryo, Mammalian Enzyme Inhibitors / toxicity Female Hippocampus / cytology Homeostasis / drug effects Luminescent Proteins / genetics Luminescent Proteins / metabolism Lysosome-Associated Membrane Glycoproteins / genetics Lysosome-Associated Membrane Glycoproteins / metabolism Macrolides / toxicity Male Mice Mice, Inbred C57BL Mice, Transgenic Microtubule-Associated Proteins / genetics Microtubule-Associated Proteins / metabolism Naphthyridines / toxicity Neurons / cytology* Neurons / drug effects Neurons / physiology* Phagosomes / metabolism
IF 5.674
Times Cited 97
Mice RBRC00806