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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 validation 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.

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Amyotrophic lateral sclerosis (ALS) is a multi-systemic, incurable, amyloid disease affecting the motor neurons, resulting in the death of patients. The disease is either sporadic or familial with SOD1, C9orf72, FUS, and TDP-43 constituting the majority of familial ALS. Multi-omics studies on patients and model systems like mice and yeast have helped in understanding the association of various signaling and metabolic pathways with the disease. The yeast model system has played a pivotal role in elucidating the gene amyloid interactions. We carried out an integrated transcriptomic and metabolomic analysis of the TDP-43 expressing yeast model to elucidate deregulated pathways associated with the disease. The analysis shows the deregulation of the TCA cycle, single carbon metabolism, glutathione metabolism, and fatty acid metabolism. Transcriptomic analysis of GEO datasets of TDP-43 expressing motor neurons from mice models of ALS and ALS patients shows considerable overlap with experimental results. Furthermore, a yeast model was used to validate the obtained results using metabolite addition and gene knock-out experiments. Taken together, our result shows a potential role for the TCA cycle, cellular redox pathway, NAD metabolism, and fatty acid metabolism in disease. Supplementation of reduced glutathione, nicotinate, and the keto diet might help to manage the disease.

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