Sorting trash from treasure: Separate pathways for autophagy and endocytic trafficking in axons

TL;DR

The paper shows that autophagy and endocytic trafficking in axons are normally separate, but α-synuclein overexpression causes them to merge, potentially leading to neuronal dysfunction in Parkinson's disease.

Contribution

The study reveals that pathogenic α-synuclein disrupts the separation between autophagy and endocytic pathways in axons.

Findings

Axonal autophagy and endocytic pathways are separate under physiological conditions.

Overexpression of α-synuclein causes autophagosomes and endosomes to merge in distal axons.

Misrouting of endocytosed cargo into autophagosomes may contribute to Parkinson's disease.

Abstract

Macroautophagy (hereafter autophagy) and endocytic trafficking are key pathways in neuronal axons that regulate the composition and integrity of the axonal proteome. These pathways have similar trafficking itineraries; however, the extent of their cross-talk remains incompletely understood. Our recent work demonstrates that under physiological conditions, axonal autophagy and endocytic pathways are separate and exhibit distinct rates of organelle maturation. Strikingly, overexpression of pathogenic α-synuclein disrupts the segregation between these pathways by merging autophagosomes and endosomes generated in the distal axon. These results raise the possibility that precocious degradation of endocytosed cargo via misrouting into lysosome-destined autophagosomes may contribute to neuronal dysfunction in Parkinson disease and related α-synucleinopathies.

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