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MassIVE MSV000088096 - Loss of TBK1 activity leads to TDP-43 proteinopathy through lysosomal dysfunction in human motor neurons
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron death accompanied by TDP-43 pathology. Haploinsufficiency of TBK1 has been found to associate with or cause ALS. However, the mechanisms by which reduced TBK1 activity contributes to human motor neuron pathology remain elusive. Here, we generated a human cellular model harboring loss-of-function mutations of TBK1 by gene editing. We performed phosphoproteomics for control and TBK1 deleted human motor neurons (hMNs) and identified the potential link between TDP-43 pathology and the dysfunctional endo-lysosomal pathway in TBK1 deleted hMNs. Moreover, prolonged lysosomal inhibition triggered TDP-43 pathology in healthy motor neurons and sensitized TBK1 patient-derived motor neurons to neurodegeneration. Together, our results revealed the mechanism of TBK1 in maintaining TDP-43 and motor neuron homeostasis, and modulating lysosomal activity was able to rescue neurodegenerative disease phenotypes caused by reduced TBK1 activity.
release_rev_6517422b-d36f-435a-959e-59e8303af5c7
by
Kevin Eggan
Published
by MassIVE.
2021
DOI
10.25345/c5dg1f
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