Tuesday, April 29, 2025

10–11 AM

46-3310 (Picower Seminar Room)

Zoom: https://mit.zoom.us/j/98400785840?pwd=az5ljtDhAzxy38pgmXxl6fcHV0rmtM.1

Title: Oligodendrocyte progenitor heterogeneity in normal aging and neurodegeneration

Abstract:

Oligodendrocyte progenitor cells (OPCs) are one of the four major glial cell types in the central nervous system (CNS). As their name suggests, OPCs are primarily defined by their capacity to differentiate into mature oligodendrocytes that form myelin sheaths around the axons in the CNS. However, OPCs continue to tile the adult CNS long after developmental myelination has concluded, and they contribute sparingly to oligodendrocyte turnover, suggesting that OPCs play important roles beyond OL replacement. To define the possible space of non-canonical OPC functions in the adult brain, I construct a transcriptomic atlas at single-cell resolution to reveal patterns of heterogeneity at local and global scales of anatomical organization. First, I characterize OPC heterogeneity in the pathologically normal human brain. I profile cells from prefrontal cortex, primary motor cortex, and striatum of 156 unique donor individuals. Across all sampled brain regions, I identify a subset of OPCs that is characterized by an angiogenic gene signature and hypothesize that these cells are perivascular OPCs that associate closely with the cerebrovascular endothelium. Furthermore, I find significant differences in gene expression between cortical and striatal OPCs which may correspond to functional specializations that support local neuronal function. Second, I profile OPCs from the dorsal striatum of four mouse models. I find a distinct reactive subpopulation whose abundance increases with age and neuropathological burden. Additionally, I perform a comparative analysis of human and mouse OPCs. OPC gene expression profiles are broadly conserved across species, but the proposed perivascular OPC signature is unique to humans. Third, I characterize OPC transcriptomic dysregulation in two human neurodegenerative proteinopathies: Huntington’s disease (HD) and Alzheimer’s disease (AD). In HD, I find that OPCs display signs of stem cell exhaustion, consistent with hypotheses of precocious OPC differentiation. In AD, I find evidence for increased mTORC2 activity and glutathione biosynthesis, reflecting a marked cellular response to oxidative stress. Together, this work deepens our understanding of OPC biology in the adult CNS and highlights areas for future study of OPC-specific contributions to neurodegenerative diseases.