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Oligodendroglial macroautophagy is essential for myelin sheath turnover to prevent neurodegeneration and death

Aber, Etan R.; Griffey, Christopher J.; Davies, Tim; Li, Alice M.; Yang, Young Joo; Croce, Katherine R.; Goldman, James E.; Grutzendler, Jaime; Canman, Julie C.; Yamamoto, Ai

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Authors

Etan R. Aber

Christopher J. Griffey

Alice M. Li

Young Joo Yang

Katherine R. Croce

James E. Goldman

Jaime Grutzendler

Julie C. Canman

Ai Yamamoto



Abstract

Although macroautophagy deficits are implicated across adult-onset neurodegenerative diseases, we understand little about how the discrete, highly evolved cell types of the central nervous system use macroautophagy to maintain homeostasis. One such cell type is the oligodendrocyte, whose myelin sheaths are central for the reliable conduction of action potentials. Using an integrated approach of mouse genetics, live cell imaging, electron microscopy, and biochemistry, we show that mature oligodendrocytes require macroautophagy to degrade cell autonomously their myelin by consolidating cytosolic and transmembrane myelin proteins into an amphisome intermediate prior to degradation. We find that disruption of autophagic myelin turnover leads to changes in myelin sheath structure, ultimately impairing neural function and culminating in an adult-onset progressive motor decline, neurodegeneration, and death. Our model indicates that the continuous and cell-autonomous maintenance of the myelin sheath through macroautophagy is essential, shedding insight into how macroautophagy dysregulation might contribute to neurodegenerative disease pathophysiology.

Citation

Aber, E. R., Griffey, C. J., Davies, T., Li, A. M., Yang, Y. J., Croce, K. R., …Yamamoto, A. (2022). Oligodendroglial macroautophagy is essential for myelin sheath turnover to prevent neurodegeneration and death. Cell Reports, 41(3), Article 111480. https://doi.org/10.1016/j.celrep.2022.111480

Journal Article Type Article
Acceptance Date Sep 19, 2022
Online Publication Date Oct 18, 2022
Publication Date 2022
Deposit Date Jan 30, 2023
Publicly Available Date Jan 30, 2023
Journal Cell Reports
Print ISSN 2211-1247
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 41
Issue 3
Article Number 111480
DOI https://doi.org/10.1016/j.celrep.2022.111480
Public URL https://durham-repository.worktribe.com/output/1182079

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