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

Vidhya Bharathi, Amandeep Girdhar, Basant K Patel

Biochimica et biophysica acta. Molecular cell research 2021 May

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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. Copyright © 2021 Elsevier B.V. All rights reserved.

Citation

Vidhya Bharathi, Amandeep Girdhar, Basant K Patel. Role of CNC1 gene in TDP-43 aggregation-induced oxidative stress-mediated cell death in S. cerevisiae model of ALS. Biochimica et biophysica acta. Molecular cell research. 2021 May;1868(6):118993