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

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., Goldman, J. E., Grutzendler, J., Canman, J. C., & 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