Elevated constitutive expression of Hsp40 chaperone Sis1 reduces TDP-43 aggregation-induced oxidative stress in Ire1 pathway dependent-manner in yeast TDP-43 proteinopathy model of amyotrophic lateral sclerosis

• Published in: Biochemical and biophysical research communications 2022-03, Vol.595, p.28-34
• Main Authors: Bharathi, Vidhya, Bajpai, Akarsh, Parappuram, Irene T., Patel, Basant K.
• Format: Article
• Language: English
• Subjects: ALS; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Gene Expression Regulation, Fungal; Hsp40; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Humans; Ire1; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Microscopy, Fluorescence; Models, Genetic; Mutation; Oxidative Stress; Protein Aggregation, Pathological - genetics; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; ROS; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Signal Transduction - genetics; Sis1; TDP-43; TDP-43 Proteinopathies - genetics; TDP-43 Proteinopathies - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.01.073

Oxidative stress is a therapeutic target in TDP-43 proteinopathies like amyotrophic lateral sclerosis (ALS) and FTLD-TDP. TDP-43 over-expression causes oxidative stress in yeast model of ALS. Previously, we developed a red/white color conversion reporter assay using ade1 or ade2 mutant yeast to examine oxidative stress induced by expression of amyloidogenic proteins. Also, a previous study showed that overexpression of yeast Hsp40 chaperone Sis1 could mitigate the toxicity and proteosomal blockage induced by TDP-43 over-expression. Here, using the red/white reporter yeast assay and also by CellROX-staining, we found that an elevated expression of Sis1 mitigates the TDP-43-induced oxidative stress. Furthermore, as redox signalling and the ER stress response pathways cross-talk, we checked if the Sis1-mediated mitigation of the TDP-43-induced oxidative stress can also be observed in yeast deleted for ER stress response gene, IRE1. We find that in the yeast deleted for the IRE1 gene, the elevated expression of Sis1 fails to neutralize the TDP-43-induced oxidative stress. Taken together, Hsp40 chaperone modulation can be further examined towards therapeutic research on the TDP-43 proteinopathies. •Elevated expression of Hsp40 Sis1 chaperone reduces TDP-43-induced oxidative stress.•Sis1 reverses the TDP-43-caused oxidative stress-induced white color to red in an ade1 mutant yeast.•Elevated Sis1expression does not reduce TDP-43-caused oxidative stress in IRE1 gene deleted yeast.•CellROX staining confirms the need of IRE1 gene for reduction of TDP-43-caused oxidative stress by Sis1.