Cell Reports
Volume 28, Issue 1, 2 July 2019, Pages 51-64.e4
Journal home page for Cell Reports

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

https://doi.org/10.1016/j.celrep.2019.06.013Get rights and content
Under a Creative Commons license
open access

Highlights

  • Degradative lysosomes are positioned along axons and abundant in axon tips

  • Soma-labeled degradative lysosomes rapidly influx into distal axons

  • Degradative lysosomes target to axonal autophagosomes and α-synuclein cargos

  • Impaired delivery of degradative lysosomes induces autophagic stress in axons

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.

Keywords

α-synuclein
axonal transport
autophagosome
autophagic stress
cathepsin
degradative lysosome
active lysosomal hydrolase
lysosomal trafficking

Cited by (0)

2

Lead Contact