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Cited by 81Autophagy in Disease and TherapyCellular transport and secretionRNA Research and Splicing

Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration

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De Pace, Raffaella, Ghosh, Saikat, Ryan, Veronica H., Sohn, Mira, Jarnik, Michal, Rezvan Sangsari, Paniz, Morgan, Nicole Y., Dale, Ryan K. +2 more·2024·Nature Neuroscience
DOI 10.1038/s41593-024-01619-1PMC PMC11156585
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Abstract

In neurons, RNA granules are transported along the axon for local translation away from the soma. Recent studies indicate that some of this transport involves hitchhiking of RNA granules on lysosome-related vesicles. In the present study, we leveraged the ability to prevent transport of these vesicles into the axon by knockout of the lysosome–kinesin adaptor BLOC-one-related complex (BORC) to identify a subset of axonal mRNAs that depend on lysosome-related vesicles for transport. We found that BORC knockout causes depletion of a large group of axonal mRNAs mainly encoding ribosomal and mitochondrial/oxidative phosphorylation proteins. This depletion results in mitochondrial defects and eventually leads to axonal degeneration in human induced pluripotent stem cell (iPSC)-derived and mouse neurons. Pathway analyses of the depleted mRNAs revealed a mechanistic connection of BORC deficiency with common neurodegenerative disorders. These results demonstrate that mRNA transport on lysosome-related vesicles is critical for the maintenance of axonal homeostasis and that its failure causes axonal degeneration.

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  • Reactive oxygen species, head injury, heat stress and pollution inhibit lysosomal function.

    “Examples of such include reactive oxygen species, head injury, heat stress and pollution inhibiting lysosomal function.48”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [48]

    The Discussion (page unavailable) describes oxidative damage to mitochondria and impaired mitophagy when axonal lysosomes are absent, but does not say that reactive oxygen species inhibit lysosomal function. Searches for head injury, heat stress, pollution, and oxidative stress did not find a passage linking any of these exposures to lysosomal inhibition. (LLM, conf=0.76)

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Authors
De Pace, R., Ghosh, S., Ryan, V. H., Sohn, M., Jarnik, M., Rezvan Sangsari, P., Morgan, N. Y., Dale, R. K., Ward, M. E., & Bonifacino, J. S.
Affiliations
National Institutes of Health (US)
Corresponding author
Bonifacino, Juan S.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2024-04-10
Volume
27
Issue
6
Pages
1087-1102
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-024-01619-1
PMC
PMC11156585
OpenAlex
W4394683841
Cited by
81
References
5
Citations by year
2026: 33 · 2025: 31 · 2024: 17
FWCI
24.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIA HD001607, ZIC HD008986)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS FI2GM142475)
  • U.S. Department of Health & Human Services | NIH | 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 › Molecular Biology › RNA Research and Splicing
Keywords
mRNA transport, BLOC-1, axonal degeneration, mitochondrial homeostasis, RNA granules, axonal translation, oxidative phosphorylation, ribosomal proteins, neurodegeneration, iPSC-derived neurons
MeSH terms
Animals, Axons, Axonal Transport, Homeostasis, Humans, Lysosomes, Mitochondria, Nerve Degeneration, Neurons, RNA, Messenger, Mice, Knockout, RNA Transport, Mice, Induced Pluripotent Stem Cells

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