Oligodendrocyte ER-phagy Restricts Excessive Myelination by Degrading Sphingolipid Synthases
- 1The University of Texas Southwestern Medical Center
Abstract
Myelination is critical for nervous system function. Numerous signaling pathways have been identified that promote myelin sheath growth, disruption of which can lead to hypomyelination, characterized by a reduction in myelin sheath thickness. However, the negative regulators of myelin sheath expansion remain poorly defined. Here, we identify a cellular brake on central nervous system myelination that restricts myelin sheath thickness during brain development. This brake is mediated by a selective form of autophagy, known as endoplasmic reticulum (ER)-phagy, which degrades the ER and its resident sphingolipid synthases. ER-phagy is highly active in oligodendrocytes during myelin membrane expansion, and its impairment leads to ER accumulation, elevated sphingolipid production, and excessive myelin thickening. Genetic reduction of de novo sphingolipid biosynthesis in the ER rescues the hypermyelination phenotype caused by ER-phagy disruption. In summary, our findings establish ER-phagy as a key regulator of sphingolipid metabolism and reveal a mechanistic link between ER homeostasis and myelin production by oligodendrocytes, providing insight into mechanisms underlying pathological hypermyelination.
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BibTeX
@misc{zhang2026oligodendrocyte,
title = {{Oligodendrocyte ER-phagy Restricts Excessive Myelination by Degrading Sphingolipid Synthases}},
author = {T. Zhang and D. Barbosa and A. Bhambri and L. O. Sun},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.04.756522},
url = {https://www.biorxiv.org/content/10.64898/2026.10.04.756522v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Oligodendrocyte ER-phagy Restricts Excessive Myelination by Degrading Sphingolipid Synthases
AU - T. Zhang
AU - D. Barbosa
AU - A. Bhambri
AU - L. O. Sun
PY - 2026
DA - 2026/10/04
PB - bioRxiv
DO - 10.64898/2026.10.04.756522
UR - https://www.biorxiv.org/content/10.64898/2026.10.04.756522v1
AB - Myelination is critical for nervous system function. Numerous signaling pathways have been identified that promote myelin sheath growth, disruption of which can lead to hypomyelination, characterized by a reduction in myelin sheath thickness. However, the negative regulators of myelin sheath expansion remain poorly defined. Here, we identify a cellular brake on central nervous system myelination that restricts myelin sheath thickness during brain development. This brake is mediated by a selective form of autophagy, known as endoplasmic reticulum (ER)-phagy, which degrades the ER and its resident sphingolipid synthases. ER-phagy is highly active in oligodendrocytes during myelin membrane expansion, and its impairment leads to ER accumulation, elevated sphingolipid production, and excessive myelin thickening. Genetic reduction of de novo sphingolipid biosynthesis in the ER rescues the hypermyelination phenotype caused by ER-phagy disruption. In summary, our findings establish ER-phagy as a key regulator of sphingolipid metabolism and reveal a mechanistic link between ER homeostasis and myelin production by oligodendrocytes, providing insight into mechanisms underlying pathological hypermyelination.
ER -