title: Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations.
abstract: 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.
authors: From the ‡Max Planck Institute for Molecular Genetics, Ihnestraβe 63-73, 14195 Berlin, Germany; meierhof@molgen.mpg.de auburger@em.uni-frankfurt.de Meierhof@molgen.mpg.de.
authors: David
authors: 0000-0002-0170-868X
authors: D
authors: Meierhofer
authors: §Experimental Neurology, Building 89, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors: Melanie
authors: M
authors: Halbach
authors: §Experimental Neurology, Building 89, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors: Nesli Ece
authors: NE
authors: Şen
authors: §Experimental Neurology, Building 89, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors: Suzana
authors: S
authors: Gispert
authors: §Experimental Neurology, Building 89, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany auburger@em.uni-frankfurt.de Meierhof@molgen.mpg.de.
authors: Georg
authors: G
authors: Auburger
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D000067698:Ataxin-2 / Q000235:genetics* / Q000378:metabolism; D001284:Atrophy; D002531:Cerebellum / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism*; D053263:Gene Regulatory Networks; D006801:Humans; D008099:Liver / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D018345:Mice, Knockout; D060066:Protein Interaction Maps; D040901:Proteomics / Q000379:methods*
chemical_list: D000597:Amino Acids, Branched-Chain; D000067698:Ataxin-2; C000593754:Atxn2 protein, mouse; D005227:Fatty Acids