Retrograde Axonal Autophagy and Endocytic Pathways Are Parallel and Separate in Neurons.

Autor:	Kulkarni VV; Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104., Stempel MH; Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104., Anand A; Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104., Sidibe DK; Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104., Maday S; Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104 smaday@pennmedicine.upenn.edu.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2022 Nov 09; Vol. 42 (45), pp. 8524-8541. Date of Electronic Publication: 2022 Sep 27.
DOI:	10.1523/JNEUROSCI.1292-22.2022
Abstrakt:	Autophagy and endocytic trafficking are two key pathways that regulate the composition and integrity of the neuronal proteome. Alterations in these pathways are sufficient to cause neurodevelopmental and neurodegenerative disorders. Thus, defining how autophagy and endocytic pathways are organized in neurons remains a key area of investigation. These pathways share many features and converge on lysosomes for cargo degradation, but what remains unclear is the degree to which the identity of each pathway is preserved in each compartment of the neuron. Here, we elucidate the degree of intersection between autophagic and endocytic pathways in axons of primary mouse cortical neurons of both sexes. Using microfluidic chambers, we labeled newly-generated bulk endosomes and signaling endosomes in the distal axon, and systematically tracked their trajectories, molecular composition, and functional characteristics relative to autophagosomes. We find that newly-formed endosomes and autophagosomes both undergo retrograde transport in the axon, but as distinct organelle populations. Moreover, these pathways differ in their degree of acidification and association with molecular determinants of organelle maturation. These results suggest that the identity of autophagic and newly endocytosed organelles is preserved for the length of the axon. Lastly, we find that expression of a pathogenic form of α-synuclein, a protein enriched in presynaptic terminals, increases merging between autophagic and endocytic pathways. Thus, aberrant merging of these pathways may represent a mechanism contributing to neuronal dysfunction in Parkinson's disease (PD) and related α-synucleinopathies. SIGNIFICANCE STATEMENT Autophagy and endocytic trafficking are retrograde pathways in neuronal axons that fulfill critical degradative and signaling functions. These pathways share many features and converge on lysosomes for cargo degradation, but the extent to which the identity of each pathway is preserved in axons is unclear. We find that autophagosomes and endosomes formed in the distal axon undergo retrograde transport to the soma in parallel and separate pathways. These pathways also have distinct maturation profiles along the mid-axon, further highlighting differences in the potential fate of transported cargo. Strikingly, expression of a pathogenic variant of α-synuclein increases merging between autophagic and endocytic pathways, suggesting that mis-sorting of axonal cargo may contribute to neuronal dysfunction in Parkinson's disease (PD) and related α-synucleinopathies. (Copyright © 2022 the authors.)
Databáze:	MEDLINE
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