Vitamin B6, B12 and folate modulate deregulated pathways and protein aggregation in yeast model of Huntington disease

• Published in: 3 Biotech 2023-03, Vol.13 (3), p.96, Article 96
• Main Authors: Pradhan, Sai Sanwid, Rao, K. Raksha, Manjunath, Meghana, Saiswaroop, R., Patnana, Durga Prasad, Phalguna, Kanikaram Sai, Choudhary, Bibha, Sivaramakrishnan, Venketesh
• Format: Article
• Language: English
• Subjects: Agglomeration; Aggregates; Agriculture; Amino acids; Autophagy; Basal ganglia; Bioinformatics; Biomaterials; Biosynthesis; Biotechnology; Cancer Research; Cell death; Chemistry; Chemistry and Materials Science; Deregulation; Disease; Fatty acids; Folic acid; Ganglia; Glutathione; Health services; Huntingtin; Huntington's disease; Huntingtons disease; Lipid metabolism; Lipids; Metabolism; Metabolomics; Neurodegenerative diseases; Nitrogen metabolism; Original; Original Article; Polyglutamine; Protein interaction; Proteins; Proteolysis; Pyridoxine; Stem Cells; Transcriptomics; Trinucleotide repeat diseases; tRNA; Ubiquitin; Vitamin B; Vitamin B6; Yeast
• ISSN: 2190-572X; 2190-5738
• DOI: 10.1007/s13205-023-03525-y

Huntington’s disease (HD) is an incurable and progressive neurodegenerative disease affecting the basal ganglia of the brain. HD is caused due to expansion of the polyglutamine tract in the protein Huntingtin resulting in aggregates. The increased PolyQ length results in aggregation of protein Huntingtin leading to neuronal cell death. Vitamin B 6 , B 12 and folate are deficient in many neurodegenerative diseases. We performed an integrated analysis of transcriptomic, metabolomic and cofactor-protein network of vitamin B 6 , B 12 and folate was performed. Our results show considerable overlap of pathways modulated by Vitamin B 6 , B 12 and folate with those obtained from transcriptomic and metabolomic data of HD patients and model systems. Further, in yeast model of HD we showed treatment of B 6 , B 12 or folate either alone or in combination showed impaired aggregate formation. Transcriptomic analysis of yeast model treated with B 6 , B 12 and folate showed upregulation of pathways like ubiquitin mediated proteolysis, autophagy, peroxisome, fatty acid, lipid and nitrogen metabolism. Metabolomic analysis of yeast model shows deregulation of pathways like aminoacyl-tRNA biosynthesis, metabolism of various amino acids, nitrogen metabolism and glutathione metabolism. Integrated transcriptomic and metabolomic analysis of yeast model showed concordance in the pathways obtained. Knockout of Peroxisomal (PXP1 and PEX7) and Autophagy (ATG5) genes in yeast increased aggregates which is mitigated by vitamin B 6 , B 12 and folate treatment. Taken together our results show a role for Vitamin B 6 , B 12 and folate mediated modulation of pathways important for preventing protein aggregation with potential implications for HD.