Jia Wang, W. Y. Ho, Kenneth J. Lim
Oct 29, 2018
Proceedings of the National Academy of Sciences
Significance TDP-43 is the defining pathological hallmark protein for two overlapping adult-onset neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 proteinopathies are also found in other major neurodegenerative diseases, such as Alzheimer’s disease, further highlighting the pivotal role of TDP-43 in the nervous system. Curiously, TDP-43 aggregates are also found in oligodendrocytes, which provide myelination and metabolic support for the neurons. Here, we show that TDP-43 is indispensable, in a cell-autonomous manner, for the proper functioning of mature oligodendrocytes, in particular, myelination and cell survival. Specifically, TDP-43 depletion leads to RIPK1-mediated necroptosis of mature oligodendrocytes and down-regulation of myelin proteins that are essential for myelination but exerts no apparent toxicity on motor neurons. TDP-43 aggregates in neurons and glia are the defining pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), raising the possibility of glial damage in the disease pathogenesis. However, the normal physiological 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 mature oligodendrocytes in mice. Although mice with TDP-43 deleted in oligodendrocytes are born in an expected Mendelian ratio, they develop progressive neurological phenotypes leading to early lethality accompanied by a progressive reduction in myelination. The progressive myelin reduction is likely due to a combination of the cell-autonomous RIPK1-mediated necroptosis of mature oligodendrocytes and the TDP-43–dependent reduction in the expression of myelin genes. Strikingly, enhanced proliferation of NG2-positive oligodendrocyte precursor cells within the white matter, but not the gray matter, was able to replenish the loss of mature oligodendrocytes, indicating an intrinsic regeneration difference between the gray and white matter oligodendrocytes. By contrast, there was no loss of spinal cord motor neurons and no sign of denervation at the neuromuscular synapses. Taken together, our data demonstrate that TDP-43 is indispensable for oligodendrocyte survival and myelination, and loss of TDP-43 in oligodendrocytes exerts no apparent toxicity on motor neurons.