Neuronal Soma-Derived Degradative Lysosomes Are Continuously Delivered to Distal Axons to Maintain Local Degradation Capacity

Abstract

Summary: Neurons face the challenge of maintaining cellular homeostasis through lysosomal degradation. While enzymatically active degradative lysosomes are enriched in the soma, their axonal trafficking and positioning and impact on axonal physiology remain elusive. Here, we characterized axon-targeted delivery of degradative lysosomes by applying fluorescent probes that selectively label active forms of lysosomal cathepsins D, B, L, and GCase. By time-lapse imaging of cortical neurons in microfluidic devices and standard dishes, we reveal that soma-derived degradative lysosomes rapidly influx into distal axons and target to autophagosomes and Parkinson disease-related α-synuclein cargos for local degradation. Impairing lysosome axonal delivery induces an aberrant accumulation of autophagosomes and α-synuclein cargos in distal axons. Our study demonstrates that the axon is an active compartment for local degradation and reveals fundamental aspects of axonal lysosomal delivery and maintenance. Our work establishes a foundation for investigations into axonal lysosome trafficking and functionality in neurodegenerative diseases. : The unique morphology of neurons presents a challenge to maintain cellular homeostasis through autophagic-lysosomal degradation. Farfel-Becker et al. reveal axon-targeted delivery and maintenance of degradative lysosomes by using lysosomal-activity-based probes in microfluidic devices and axons as an active compartment for local degradation. Impairing lysosome axonal delivery induces distal autophagic stress. Keywords: α-synuclein, axonal transport, autophagosome, autophagic stress, cathepsin, degradative lysosome, active lysosomal hydrolase, lysosomal trafficking