FUNCTIONS AND MECHANISMS UNDERLYING THE ESSENTIAL ROLES OF TDP-43, AN ALS/FTD PATHOLOGICAL SIGNATURE PROTEIN IN OLIGODENDROCYTES

Abstract

TDP-43 aggregates, the pathological hallmarks of amyotrophic lateral sclerosis and frontotemporal dementia, are observed in both neurons and glia, raising the possibility of glial damage in disease pathogenesis. However, functions of TDP-43 in glia are largely unknown. To address how TDP-43 may be required for oligodendroglial functions, we selectively deleted TDP-43 in oligodendrocytes in mice. These mice developed progressive motor deficits, early lethality, and progressive myelin reduction, which is at least partially due to loss of oligodendrocytes and cholesterol metabolism disruption. Depletion of TDP-43 led to downregulation of SREBF2, the master regulator of cholesterol metabolism, and genes involved in cholesterol biosynthesis and uptake, suggesting a potential regulation of cholesterol metabolism by TDP-43. Taken together, our data suggest TDP-43 is indispensable for oligodendrocyte survival, as well as myelination via maintaining SREBF2-dependent cholesterol homeostasis.