Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology

TDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal lobar degeneration (FTLD). Namely, both diseases feature aggregated and phosphorylated TDP-43 containing inclusions in the cytoplasm and a loss of nuclear TDP-43 in affected neurons. It has been reported that ta...

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Autores principales:	Yuan Tian, Yi Wang, Angela M. Jablonski, Yinghui Hu, Jonathan A. Sugam, Markus Koglin, Shawn J. Stachel, Heather Zhou, Jason M. Uslaner, Sophie Parmentier-Batteur
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	TTBK1 ALS FTLD TDP-43 Pathology Phosphorylation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/10127822ae8a4b869c780c0f430e8e11
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spelling	oai:doaj.org-article:10127822ae8a4b869c780c0f430e8e112021-12-04T04:33:12ZTau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology1095-953X10.1016/j.nbd.2021.105548https://doaj.org/article/10127822ae8a4b869c780c0f430e8e112021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0969996121002977https://doaj.org/toc/1095-953XTDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal lobar degeneration (FTLD). Namely, both diseases feature aggregated and phosphorylated TDP-43 containing inclusions in the cytoplasm and a loss of nuclear TDP-43 in affected neurons. It has been reported that tau tubulin kinase (TTBK)1/2 phosphorylate TDP-43 and TTBK1/2 overexpression induced neuronal loss and behavioral deficits in a C. elegans model of ALS. Here we aimed to elucidate the molecular mechanisms of TTBK1 in TDP-43 pathology. TTBK1 levels were observed to be elevated in ALS patients' post-mortem motor cortex. Also, TTBK1 was found to phosphorylate TDP-43 at disease-relevant sites in vitro directly, and this phosphorylation accelerated TDP-43 formation of high molecular species. Overexpression of TTBK1 in mammalian cells induced TDP-43 phosphorylation and the construction of high molecular species, concurrent with TDP-43 mis-localization and cytoplasmic inclusions. In addition, when TTBK1 was knocked down or pharmacologically inhibited, TDP-43 phosphorylation and aggregation were significantly alleviated. Functionally, TTBK1 knockdown could rescue TDP-43 overexpression-induced neurite and neuronal loss in iPSC-derived GABAergic neurons. These findings suggest that phosphorylation plays a critical role in the pathogenesis of TDP-43 pathology and that TTBK1 inhibition may have therapeutic potential for the treatment of ALS and FTLD.Yuan TianYi WangAngela M. JablonskiYinghui HuJonathan A. SugamMarkus KoglinShawn J. StachelHeather ZhouJason M. UslanerSophie Parmentier-BatteurElsevierarticleTTBK1ALSFTLDTDP-43PathologyPhosphorylationNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENNeurobiology of Disease, Vol 161, Iss , Pp 105548- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TTBK1 ALS FTLD TDP-43 Pathology Phosphorylation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	TTBK1 ALS FTLD TDP-43 Pathology Phosphorylation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Yuan Tian Yi Wang Angela M. Jablonski Yinghui Hu Jonathan A. Sugam Markus Koglin Shawn J. Stachel Heather Zhou Jason M. Uslaner Sophie Parmentier-Batteur Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology
description	TDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal lobar degeneration (FTLD). Namely, both diseases feature aggregated and phosphorylated TDP-43 containing inclusions in the cytoplasm and a loss of nuclear TDP-43 in affected neurons. It has been reported that tau tubulin kinase (TTBK)1/2 phosphorylate TDP-43 and TTBK1/2 overexpression induced neuronal loss and behavioral deficits in a C. elegans model of ALS. Here we aimed to elucidate the molecular mechanisms of TTBK1 in TDP-43 pathology. TTBK1 levels were observed to be elevated in ALS patients' post-mortem motor cortex. Also, TTBK1 was found to phosphorylate TDP-43 at disease-relevant sites in vitro directly, and this phosphorylation accelerated TDP-43 formation of high molecular species. Overexpression of TTBK1 in mammalian cells induced TDP-43 phosphorylation and the construction of high molecular species, concurrent with TDP-43 mis-localization and cytoplasmic inclusions. In addition, when TTBK1 was knocked down or pharmacologically inhibited, TDP-43 phosphorylation and aggregation were significantly alleviated. Functionally, TTBK1 knockdown could rescue TDP-43 overexpression-induced neurite and neuronal loss in iPSC-derived GABAergic neurons. These findings suggest that phosphorylation plays a critical role in the pathogenesis of TDP-43 pathology and that TTBK1 inhibition may have therapeutic potential for the treatment of ALS and FTLD.
format	article
author	Yuan Tian Yi Wang Angela M. Jablonski Yinghui Hu Jonathan A. Sugam Markus Koglin Shawn J. Stachel Heather Zhou Jason M. Uslaner Sophie Parmentier-Batteur
author_facet	Yuan Tian Yi Wang Angela M. Jablonski Yinghui Hu Jonathan A. Sugam Markus Koglin Shawn J. Stachel Heather Zhou Jason M. Uslaner Sophie Parmentier-Batteur
author_sort	Yuan Tian
title	Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology
title_short	Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology
title_full	Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology
title_fullStr	Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology
title_full_unstemmed	Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology
title_sort	tau-tubulin kinase 1 phosphorylates tdp-43 at disease-relevant sites and exacerbates tdp-43 pathology
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/10127822ae8a4b869c780c0f430e8e11
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Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology

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