ALS-FTD signature protein TDP-43 regulates myelination and is required for oligodendrocyte survivals Jia Wang1, Wan Yun HO1, Klaus-Armin Nave4, Shuo-Chien Ling1,2,3*, 1Department of Physiology,2Neurobiology/Ageing Programme, National University of Singapore, 117549, Singapore; 3Program in Neuroscience and Behavior Disorders, Duke-NUS Medical School, 169857, Singapore; 4Department of Neurogenetics, Max Planck Institute of Experimental medicine, Gottingen, Germany *Corresponding Author
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 is 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 Mendelian ratio, they develop progressive neurological phenotypes leading to early lethality accompanied by progressive reduction in myelination. The myelin reduction is at least in part due to the cell-autonomous RIPK1-dependent necroptosis of oligodendrocytes. Strikingly, enhanced proliferation of NG2-positive oligodendrocyte precursor cells within the white matter, but not the grey matter, were able to replenish the loss of mature oligodendrocytes, indicating an intrinsic difference between the regeneration capacities of the grey and white matter oligodendrocytes. By contrast, neuromuscular synapses are intact with no loss of spinal cord motor neurons in these mice. Taken together, we showed, for the first time, that TDP-43 is indispensable for oligodendrocyte survival and functions, and loss of TDP-43 in oligodendrocytes exert no apparent toxic effects to motor neurons.
Funding: National Medical Research Council (NMRC/OFIRG/0001/2016 and NMRC/OFIRG/0042/2017) and Ministry of Education (MOE2016-T2-1-024), Singapore to S.-C. L.
Credits: None available.
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