Motor System Oligodendroglia Atlas Reveals Activation States Associated with Region-Specific Vulnerability in ALS

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 neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Yet their diversity and disease relevance in the central nervous system remain incompletely defined. 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 ALS patients. We identify a previously unrecognized 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 novel transcriptional oligodendrocyte marker and find LRP2 and MBP proteins to be elevated in ALS cerebrospinal fluid (CSF), offering a potential biomarker of oligodendrocyte dysfunction. Our study provides a systems-level framework to interpret oligodendrocyte and OPC changes in ALS, linking cell state shifts to molecular alterations that can guide biomarker and therapeutic strategies.