Integrated multi-omic analysis of Huntington disease and yeast model delineates pathways modulating protein aggregation

Sai Sanwid Pradhan, Sai Manohar Thota, R. Saiswaroop, Sai Krishna Srimadh Bhagavatham, Sujith Kumar Pulukool, Sriram Rathnakumar, Kanikaram Sai Phalguna, Rajesh Babu Dandamudi, Ashish Pargaonkar, Prasanth Joseph, Joshy E. V., Venketesh Sivaramakrishnan
2022 Disease Models & Mechanisms  
Huntington's disease (HD) is a neurodegenerative disease associated with polyglutamine expansion in the protein Huntingtin. Though the polyglutamine repeat length correlates with the age of onset and severity, the complication points to disease modifiers. Mitochondrial dysfunction and metabolic deregulation are associated with the disease. Despite multi-omic characterization of patients and model systems, the mechanisms have remained elusive. Systems analysis of multi-omics data and its
more » ... on using yeast model could help to elucidate pathways that modulate protein aggregation. Metabolomic analysis of HD patients and yeast model of HD was carried out. Our analysis shows a considerable overlap of deregulated metabolic pathways. Further, our multi-omic analysis shows deregulated pathways that are common to human, mice and yeast model systems and those that are unique to them. The deregulated pathways include metabolism of various amino acids, glutathione metabolism, longevity, autophagy and mitophagy. Addition of selected metabolites and gene knockout from the deregulated pathways in yeast model system shows that they modulate protein aggregation. Taken together our results show modulation of deregulated pathways influences protein aggregation in HD with implications for progression and prognosis.
doi:10.1242/dmm.049492 pmid:36052548 fatcat:nqykyweqyjbtje3ktjuldhn3ce