De mate van activatie van oligodendrocyten bepaalt hun kwetsbaarheid in het menselijk centraal zenuwstelsel.

Oligodendrocytes, the second most abundant cell type in the motor cortex and the most abundant in the spinal cord, are increasingly recognized as active contributors to diseases, including neurodegeneration. Yet their diversity and disease relevance in the central nervous system remain incompletely defined. Across studies spanning neurodegeneration, demyelination, psychiatric, and systemic conditions, a convergent pattern emerges, where oligodendrocytes lose mature myelinating capacity while progenitors proliferate but fail to differentiate, cycling through a shared stress-response program. This cross-disease transcriptional convergence reframes remyelination failure as a maturation and differentiation problem rather than a proliferative one, and identifies a conserved set of molecular markers as candidate hubs for therapeutic intervention. Here, we generate a comprehensive single-nucleus transcriptomic atlas of 176 samples, integrating 2 in-house and 16 publicly available datasets. It encompasses more than 1,000,000 cells (350,000 oligodendrocytes and oligodendrocyte precursors) from the human motor cortex and spinal cord in non-neurological controls and amyotrophic lateral sclerosis (ALS) patients. We identify a previously undescribed oligodendrocyte subpopulation—marked by PPEF1—and uncover regional differences, with distinct OPALIN+ and RBFOX1+ oligodendrocyte proportions between cortex and spinal cord. Importantly, we demonstrate that “disease-associated oligodendrocytes” (DAOs) represent a distinct activation state, rather than a distinct subpopulation. In ALS, spinal cord oligodendrocytes selectively shift toward reactive states, characterized by JUND-enriched regulon activity, heightened metabolic demand, increased intercellular signaling, and activation of cell-death pathways. Finally, we identify LRP2 as a transcriptional oligodendrocyte marker and find LRP2 and MBP proteins to be elevated in ALS cerebrospinal fluid (CSF), establishing candidate biomarkers of oligodendrocyte perturbation. Our study provides a systems-level framework to interpret oligodendrocyte and OPC alterations in disease, linking cell state shifts to molecular alterations that can guide biomarker and therapeutic strategies.