Ataxin-2 (Atxn2)-knock-out mice show branched chain amino acids and fatty acids pathway alterations

  • Human Ataxin-2 (ATXN2) gene locus variants have been associated with obesity, diabetes mellitus type 1,and hypertension in genome-wide association studies, whereas mouse studies showed the knock-out of Atxn2 to lead to obesity, insulin resistance, and dyslipidemia. Intriguingly, the deficiency of ATXN2 protein orthologs in yeast and flies rescues the neurodegeneration process triggered by TDP-43 and Ataxin-1 toxicity. To understand the molecular effects of ATXN2 deficiency by unbiased approaches, we quantified the global proteome and metabolome of Atxn2-knock-out mice with label-free mass spectrometry. In liver tissue, significant downregulations of the proteins ACADS, ALDH6A1, ALDH7A1, IVD, MCCC2, PCCA, OTC, together with bioinformatic enrichment of downregulated pathways for branched chain and other amino acid metabolism, fatty acids, and citric acid cycle were observed. Statistical trends in the cerebellar proteome and in the metabolomic profiles supported these findings. They are in good agreement with recent claims that PBP1, the yeast ortholog of ATXN2, sequestrates the nutrient sensor TORC1 in periods of cell stress. Overall, ATXN2 appears to modulate nutrition and metabolism, and its activity changes are determinants of growth excess or cell atrophy.
Author:David MeierhoferORCiDGND, Melanie HalbachGND, Nesli Ece ŞenGND, Suzana Gispert, Georg AuburgerORCiDGND
Pubmed Id:
Parent Title (English):Molecular & cellular proteomics
Publisher:The American Society for Biochemistry and Molecular Biology
Place of publication:Bethesda, Md.
Document Type:Article
Date of Publication (online):2016/12/01
Date of first Publication:2016/02/05
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/12/01
Page Number:12
First Page:1728
Last Page:1739
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Author’s Choice—Final version free via Creative Commons CC-BY license.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0