Role of CNC1 gene in TDP-43 aggregation-induced oxidative stress-mediated cell death in S. cerevisiae model of ALS

Bharathi, V. and Patel, B. K. and et al, . (2021) Role of CNC1 gene in TDP-43 aggregation-induced oxidative stress-mediated cell death in S. cerevisiae model of ALS. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1868 (6). p. 118993. ISSN 01674889

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Abstract

TDP-43 protein is found deposited as inclusions in the amyotrophic lateral sclerosis (ALS) patient's brain. The mechanism of neuron death in ALS is not fully deciphered but several TDP-43 toxicity mechanisms such as mis-regulation of autophagy, mitochondrial impairment and generation of oxidative stress etc., have been implicated. A predominantly nuclear protein, Cyclin C, can regulate the oxidative stress response via transcription of stress response genes and also by translocation to the cytoplasm for the activation of mitochondrial fragmentation-dependent cell death pathway. Using the well-established yeast TDP-43 proteinopathy model, we examined here whether upon TDP-43 aggregation, cell survival depends on the CNC1 gene that encodes the Cyclin C protein or other genes which encode proteins that function in conjunction with Cyclin C, such as DNM1, FIS1 and MED13. We show that the TDP-43's toxicity is significantly reduced in yeast deleted for CNC1 or DNM1 genes and remains unaltered by deletions of genes, FIS1 and MED13. Importantly, this rescue is observed only in presence of functional mitochondria. Also, deletion of the YBH3 gene involved in the mitochondria-dependent apoptosis pathway reduced the TDP-43 toxicity. Deletion of the VPS1 gene involved in the peroxisomal fission pathway did not mitigate the TDP-43 toxicity. Strikingly, Cyclin C-YFP was observed to relocate to the cytoplasm in response to TDP-43's co-expression which was prevented by addition of an anti-oxidant molecule, N-acetyl cysteine. Overall, the Cyclin C, Dnm1 and Ybh3 proteins are found to be important players in the TDP-43-induced oxidative stress-mediated cell death in the S. cerevisiae model.

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IITH Creators:

IITH Creators	ORCiD
Patel, Basant Kumar	http://orcid.org/0000-0001-9465-4803

Item Type:

Article

Uncontrolled Keywords:

amyotrophic lateral sclerosis; animal experiment; animal model; apoptosis; Article; carbon source; cell survival; cellular distribution; cnc1 gene; controlled study; fis1 gene; flow cytometry; gene; gene deletion; gene disruption; homologous recombination; human; med13 gene; mitochondrial respiration; molecular weight; mouse; nonhuman; nuclear localization signal; outer membrane; oxidative stress; plasmid; priority journal; promoter region; protein aggregation; protein degradation; protein expression; Saccharomyces cerevisiae; staining; TDP 43 proteinopathy; Western blotting; yeast cell

Subjects:

Others > Biotechnology

Divisions:

Department of Biotechnology

Depositing User:

. LibTrainee 2021

Date Deposited:

07 Jul 2021 09:46

Last Modified:

24 Feb 2022 10:22

URI:

http://raiithold.iith.ac.in/id/eprint/8160