Integrated Multi-Omic Data Analysis and Validation with Yeast Model Show Oxidative Phosphorylation Modulate Protein Aggregation in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis is a progressive, incurable amyloid aggregating neurodegenerative disease involving the motor neurons. Identification of potential biomarkers and therapeutic targets can assist in the better management of the disease. We used an integrative approach encompassing analysis of transcriptomic datasets of human and mice from GEO database. Our analysis of ALS patient datasets showed deregulation in Non-alcoholic fatty acid liver disease and oxidative phosphorylation. Transgenic mice datasets pertaining to SOD1, FUS and TDP-43 showed deregulation in oxidative phosphorylation and ribosome associated pathways. Commonality analysis between the human and mice datasets showed oxidative phosphorylation as a major deregulated pathway among the different datasets. Further, gene expression analysis of mitochondrial electron transport chain show downregulation of genes belonging to Complex I and IV. The results were then validated using the yeast model system. Inhibitor studies using metformin (complex-I inhibitor) and malonate (complex-II inhibitor) did not have any effect in mitigating the amyloids while antimycin (complex-III inhibitor) and azide (complex-IV inhibitor) reduced amyloidogenesis. Knock-out of QCR8 (complex-III) or COX8 (complex–IV) completely cleared the amyloids. Taken together, our results show a critical role for mitochondrial oxidative phosphorylation in amyloidogenesis and as a potential therapeutic target in ALS.