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

Sai Sanwid Pradhan; K Raksha Rao; Meghana Manjunath; R Saiswaroop; Durga Prasad Patnana; Kanikaram Sai Phalguna; Bibha Choudhary; Venketesh Sivaramakrishnan

doi:10.1007/s13205-023-03525-y

Vitamin B_6, B₁₂ and folate modulate deregulated pathways and protein aggregation in yeast model of Huntington disease

3 Biotech. 2023 Mar;13(3):96. doi: 10.1007/s13205-023-03525-y. Epub 2023 Feb 24.

Authors

Sai Sanwid Pradhan¹, K Raksha Rao², Meghana Manjunath², R Saiswaroop¹, Durga Prasad Patnana³, Kanikaram Sai Phalguna¹, Bibha Choudhary^#², Venketesh Sivaramakrishnan^#¹

Affiliations

¹ Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, Anantapur, Andhra Pradesh 515134 India.
² Institute of Bioinformatics and Applied Biotechnology, Bangalore, Karnataka 560100 India.
³ Department of Chemistry, Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, Anantapur, Andhra Pradesh 515134 India.

^# Contributed equally.

Abstract

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 B₆, B₁₂ and folate are deficient in many neurodegenerative diseases. We performed an integrated analysis of transcriptomic, metabolomic and cofactor-protein network of vitamin B₆, B₁₂ and folate was performed. Our results show considerable overlap of pathways modulated by Vitamin B₆, B₁₂ 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 B₆, B₁₂ or folate either alone or in combination showed impaired aggregate formation. Transcriptomic analysis of yeast model treated with B₆, B₁₂ 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 B₆, B₁₂ and folate treatment. Taken together our results show a role for Vitamin B₆, B₁₂ and folate mediated modulation of pathways important for preventing protein aggregation with potential implications for HD.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-023-03525-y.

Keywords: Autophagy; Cofactor protein interaction; Huntingtin; Huntington disease; Metabolomics; Neurodegeneration; Transcriptomics.

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