Defining the Early Response of Oligodendrocyte-Lineage Cells to Traumatic CNS Axonal Injury

Injured central nervous system axons rarely regenerate or remyelinate efficiently. Oligodendrocyte (OL) -lineage cells influence both processes, yet their early response to axonal injury remains incompletely defined. Using an optic nerve crush model in male and female mice, we profiled acute OL-lineage responses over the first week at morphological, translatomic, and proteomic levels. Oligodendrocyte precursor cells (OPCs) became activated and their number increased without immediate maturation, while mature OLs developed fragmented, degenerating processes. Lineage-restricted translatomic profiling revealed extensive remodeling that converged on disease-associated OL programs. OL-specific proximity proteomics together with the OL-lineage translatome, identified Perilipin 4 (Plin4), a lipid-droplet coat protein, as a novel regulator of OL-lineage homeostasis. Plin4 loss was associated with increased numbers of OPCs, fewer differentiated OLs, and increased lipid peroxidation. Our results suggest Plin4 contributes to the lipid homeostasis required for OPC differentiation and cell survival. Together, our findings define the early, traumatic injury-driven responses of the OL lineage and identify Plin4 as a novel regulator of OL lineage homeostasis. Significance Statement This work defines the early, traumatic injury-driven responses of oligodendrocyte-lineage cells, and identifies Plin4 as a novel regulator of oligodendrocyte homeostasis.