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Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy.

Abstract：

:Though motor neurons selectively degenerate in amyotrophic lateral sclerosis, other cell types are likely involved in this disease. We recently generated rNLS8 mice in which human TDP-43 (hTDP-43) pathology could be reversibly induced in neurons and expected that microglia would contribute to neurodegeneration. However, only subtle microglial changes were detected during disease in the spinal cord, despite progressive motor neuron loss; microglia still reacted to inflammatory triggers in these mice. Notably, after hTDP-43 expression was suppressed, microglia dramatically proliferated and changed their morphology and gene expression profiles. These abundant, reactive microglia selectively cleared neuronal hTDP-43. Finally, when microgliosis was blocked during the early recovery phase using PLX3397, a CSF1R and c-kit inhibitor, rNLS8 mice failed to regain full motor function, revealing an important neuroprotective role for microglia. Therefore, reactive microglia exert neuroprotective functions in this amyotrophic lateral sclerosis model, and definition of the underlying mechanism could point toward novel therapeutic strategies.

journal_name

Nat Neurosci

journal_title

Nature neuroscience

authors

Spiller KJ,Restrepo CR,Khan T,Dominique MA,Fang TC,Canter RG,Roberts CJ,Miller KR,Ransohoff RM,Trojanowski JQ,Lee VM

doi

10.1038/s41593-018-0083-7

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

329-340

issue

3

eissn

1097-6256

issn

1546-1726

pii

10.1038/s41593-018-0083-7

journal_volume

21

pub_type

杂志文章

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