Integrated multi-omic data analysis and validation with yeast model show oxidative phosphorylation modulates protein aggregation in amyotrophic lateral sclerosis

J Biomol Struct Dyn. 2022 Jun 24;1-20. doi: 10.1080/07391102.2022.2090441. Online ahead of print.

Abstract

Amyotrophic Lateral Sclerosis is a progressive, incurable amyloid aggregating neurodegenerative disease involving the motor neurons. Identifying 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 the GEO database. Our analysis of ALS patient datasets showed deregulation in Non-alcoholic fatty acid liver disease and oxidative phosphorylation. Transgenic mice datasets of 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. Further, protein-protein and protein-drug interaction network analysis of mitochondrial electron transport chain showed enrichment of proteins and inhibitors of mitochondrial Complex III and IV. The results were further validated using the yeast model system. Inhibitor studies using metformin (Complex-I inhibitor) and malonate (Complex-II inhibitor) did not show 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) 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.Communicated by Ramaswamy H. Sarma.

Keywords: ALS; FUS; SOD1; Systems analysis; TDP-43; mitochondrial dysfunction; oxidative phosphorylation; transcriptomics.