Integrated multi-omics analysis of Huntington disease identifies pathways that modulate protein aggregation

Abstract

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.

Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy

“…In 2022, the multi-omics of human, mice, and yeast HD model systems also underlined the deregulation of glycolysis, TCA cycle, and pyruvate metabolism in HD datasets, which was in line with previous studies [ 200 , 201 , 202 ]. This study also indicated lower levels of alanine in HD patients, as well as in HD mouse model systems.…”

Integrated Omic Analysis Delineates Pathways Modulating Toxic TDP-43 Protein Aggregates in Amyotrophic Lateral Sclerosis

“…Further, metabolic addition experiments and gene knock-out studies were used to validate the role of deregulated pathways in amyloidogenesis. We have performed similar studies on other metabolic and auto-immune diseases such as Huntington's disease, glaucoma, rheumatoid arthritis, and avascular necrosis [24,[28][29][30][31]. Our current study showed that fatty acid degradation, TCA cycle, nicotinate, and nicotinamide metabolism as the major perturbed pathways that could modulate amyloidogenesis in TDP-43-induced ALS.…”

“…Genome-wide analysis using siRNA, or yeast knock-out or over-expression libraries have proved to be critical to understanding the role of genes with either protein aggregation or its toxicity [23]. Using a yeast model, a role for deregulated pathways in the aggregation of mutant Huntington's has been demonstrated [24]. Yeast is used as a good model system to understand protein aggregation in many amyloid diseases, including ALS [25].…”

Integrated multi-omics analysis of Alzheimer’s disease shows molecular signatures associated with disease progression and potential therapeutic targets

“…mice model of AD has shown that KO of complex III gene led to reduce a-beta aggregation 88 . Similarly, KO of genes involved in mitochondrial fission helped to clear protein aggregates in yeast model of HD 89 . Activation of immune cells leads to metabolic remodelling 90 .…”