Oligodendroglial Densities and Myelin Structure Are Altered in TDP-43 Related Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons. However, the surrounding glia, including oligodendrocytes, also exhibit ALS pathology and TDP-43 related dysfunction. Given that oligodendrocytes, the myelinating cells of the central nervous system, are essential for motor neuron function, they may play an underappreciated role in ALS. Here, we have extensively characterized the oligodendrocyte lineage and myelin integrity in the TDP-43^Q331K mouse model of ALS. In the lumbar spinal cord of end-stage male TDP-43^Q331K mice (TDP-43), compared to wild-type littermates (WT), oligodendrocyte precursor cell (OPC) density, oligodendrocyte proliferation, and differentiation were all increased. There was no correlative increase in the density of mature oligodendrocytes, which was determined to be due to an increase in oligodendroglial apoptosis. In end-stage mice, myelin reflectance was increased in the dorsal column of TDP-43 mice, while electron microscopy showed myelin damage and misfolding in the TDP-43 mice. Our data suggest that the oligodendrocyte lineage is impacted in TDP-43 related ALS.