Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology.
Autor: | Tian Y; Neuroscience, MRL, Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: yuan.tian1@merck.com., Wang Y; Neuroscience, MRL, Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA., Jablonski AM; Neuroscience, MRL, Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA., Hu Y; Neuroscience, MRL, Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA., Sugam JA; Neuroscience, MRL, Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA., Koglin M; Mass Spectrometry & Biophysics, MRL, Merck & Co., Inc, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA., Stachel SJ; Chemistry, MRL, Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA., Zhou H; Genetics and Pharmacogenomics, MRL, Merck & Co., Inc, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA., Uslaner JM; Neuroscience, MRL, Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA., Parmentier-Batteur S; Neuroscience, MRL, Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA 19486, USA. |
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Jazyk: | angličtina |
Zdroj: | Neurobiology of disease [Neurobiol Dis] 2021 Dec; Vol. 161, pp. 105548. Date of Electronic Publication: 2021 Nov 06. |
DOI: | 10.1016/j.nbd.2021.105548 |
Abstrakt: | 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. (Copyright © 2021 Merck Sharp & Dohme Corp. Published by Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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