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Cited by 152Autophagy in Disease and TherapyCellular transport and secretionCalcium signaling and nucleotide metabolism

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

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Farfel-Becker, Tamar, Roney, Joseph C., Cheng, Xiu-Tang, Li, Sunan, Cuddy, Sean R., Sheng, Zu-Hang·2019·Cell Reports
DOI 10.1016/j.celrep.2019.06.013PMC PMC6696943
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Abstract

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.

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  • Impairment of mitophagy has been implicated in disease through strong genetic links with PD, specifically the genes LRRK2, PARKIN, and PINK1.

    “Impairment of mitophagy has been implicated in disease through strong genetic links with PD, specifically the genes LRRK2, PARKIN, and PINK1.51–55”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [53]

    The Results section links impaired axonal lysosome delivery to accumulation of a Parkinson’s-associated α-synuclein mutant, not to impaired mitophagy or genetic risk from LRRK2, PARKIN, and PINK1. The References list names a study of PINK1- and Parkin-dependent mitophagy, but our copy does not make the claimed genetic link to Parkinson’s disease; a search for LRRK2 found no relevant passage. No page numbers are available in our copy. (LLM, conf=0.76)

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Cited by

Sorted by citations

Authors
Farfel-Becker, T., Roney, J. C., Cheng, X.-T., Li, S., Cuddy, S. R., & Sheng, Z.-H.
Affiliations
National Institutes of Health (US)
Corresponding author
Sheng, Zu-Hang
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2019-07
Volume
28
Issue
1
Pages
51-64.e4
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2019.06.013
PMC
PMC6696943
OpenAlex
W2954000601
Cited by
152
References
5
Citations by year
2026: 14 · 2025: 27 · 2024: 15 · 2023: 19 · 2022: 35 · 2021: 26 · 2020: 15 · 2019: 1
FWCI
14.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Institute of Neurological Disorders and Stroke
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
lysosomal trafficking, autophagosomes, alpha-synuclein, Parkinson's disease, lysosomal cathepsins, lysosomal enzyme delivery, neuronal soma, microfluidic imaging, neurodegeneration
MeSH terms
Autophagosomes, Animals, Autophagy, Axons, Axonal Transport, Cathepsins, Female, Ganglia, Spinal, Glucosylceramidase, Homeostasis, Humans, Lysosomes, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Neurons, ADP-Ribosylation Factors, Protein Transport, Mice, alpha-Synuclein, HEK293 Cells

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