Activation of the yeast MAP kinase, Slt2, protects against TDP-43 and TDP-25 toxicity in the Saccharomyces cerevisiae proteinopathy model.

Autor: Bajpai A; Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana, 502284, India., Bharathi V; Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana, 502284, India., Kumawat R; Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, 462066, India., Tomar RS; Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, 462066, India., Patel BK; Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana, 502284, India. Electronic address: basantkpatel@bt.iith.ac.in.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Dec 31; Vol. 741, pp. 151062. Date of Electronic Publication: 2024 Nov 23.
DOI: 10.1016/j.bbrc.2024.151062
Abstrakt: TDP-43 proteinopathy is observed in human neurodegenerative diseases like ALS. Heterologous TDP-43 expression in the yeast model also mimics several proteinopathy features such as cytotoxicity, cytoplasmic mis-localization and oxidative stress. Among the pathways implicated in modulating the TDP-43 toxicity in yeast, the unfolded protein response (UPR) activation was also identified. Here, we examine the role of stress-regulated yeast MAP kinase, Slt2, which also links cellular stress with UPR activation, in modulating the toxicities of the full-length TDP-43 and its 25 kDa C-terminal fragment, TDP-25. We find enhancement in the cytotoxicity of TDP-43, as well as TDP-25, in the yeast cells deleted for the MAP kinase, Slt2, but not in those lacking other yeast MAP kinases, Kss1 and Fus3. Unlike in the wild-type yeast, upon treatment with an antioxidant N-acetyl cysteine, the TDP-43 toxicity could not be mitigated in the slt2Δ yeast but the TDP-25 toxicity was significantly rescued suggesting oxidative stress as an important contributor to the TDP-25 toxicity. Notably, TDP-43 as well as TDP-25 expressions could cause significant phosphorylation of Slt2 suggesting activation of this MAP Kinase due to their toxicities. Interestingly, in the slt2Δ cells, lacking the MAP Kinase activity, a treatment with low concentrations of an UPR activator molecule, DTT, caused significant reduction in the toxicities of both TDP-43 as well as TDP-25. Taken together, these findings suggest that TDP-43 and TDP-25 toxicity-induced stress-mediated activation of the MAP kinase Slt2 helps in mitigating their toxicities in the yeast model possibly through UPR activation.
Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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