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Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):E10941-E10950. doi: 10.1073/pnas.1809821115. Epub 2018 Oct 29.

Cell-autonomous requirement of TDP-43, an ALS/FTD signature protein, for oligodendrocyte survival and myelination.

Author information

1
Department of Physiology, National University of Singapore, Republic of Singapore 117549.
2
Department of Biological Sciences, National University of Singapore, Republic of Singapore 117549.
3
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Gottingen, Germany.
4
Department of Physiology, National University of Singapore, Republic of Singapore 117549; shuochien@gmail.com.
5
Neurobiology/Ageing Programme, National University of Singapore, Republic of Singapore 117549.
6
Program in Neuroscience and Behavior Disorders, Duke-NUS Medical School, Republic of Singapore 169857.

Abstract

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.

KEYWORDS:

TDP-43; amyotrophic lateral sclerosis; frontotemporal dementia; necroptosis; oligodendrocyte

PMID:
30373824
PMCID:
PMC6243235
[Available on 2019-05-13]
DOI:
10.1073/pnas.1809821115
[Indexed for MEDLINE]

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