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• W2257662942 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. 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. Ataxin-2 (ATXN2) 1The abbreviations used are:Atxn2Ataxin-2FAFormic acidFDRFalse discovery rateGSEAGene Set Enrichment AnalysisHILICHydrophilic interaction chromatographyKOKnock outLFQLabel free quantificationMeOHMethanolMRMMultiple Reaction MonitoringMTBEMethyl-tert-butyl esterPEPPosterior error probabilityPPIProtein–protein interactionRPReversed phaseSTRINGSearch Tool for the Retrieval of Interacting Genes/Proteins. is a stress-regulated protein of 124 kDa size, which is expressed in specific neuron populations, but also in hepatocytes (1Scoles D.R. Pflieger L.T. Thai K.K. Hansen S.T. Dansithong W. Pulst S.M. ETS1 regulates the expression of ATXN2.Hum. Mol. Genet. 2012; 21: 5048-5065Crossref PubMed Scopus (22) Google Scholar, 2Huynh D.P. Del Bigio M.R. Ho D.H. Pulst S.M. Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer's disease and spinocerebellar ataxia 2.Ann. Neurol. 1999; 45: 232-241Crossref PubMed Scopus (150) Google Scholar, 3Nonhoff U. Ralser M. Welzel F. Piccini I. Balzereit D. Yaspo M.L. Lehrach H. Krobitsch S. Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules.Mol. Biol. Cell. 2007; 18: 1385-1396Crossref PubMed Scopus (252) Google Scholar, 4Fittschen M. Lastres-Becker I. Halbach M.V. Damrath E. Gispert S. Azizov M. Walter M. Muller S. Auburger G. Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate.Neurogenetics. 2015; 16: 181-192Crossref PubMed Scopus (48) Google Scholar). The structure of the human ATXN2 protein is characterized (1Scoles D.R. Pflieger L.T. Thai K.K. Hansen S.T. Dansithong W. Pulst S.M. ETS1 regulates the expression of ATXN2.Hum. Mol. Genet. 2012; 21: 5048-5065Crossref PubMed Scopus (22) Google Scholar) by the N-terminal polyQ domain (5Sahba S. Nechiporuk A. Figueroa K.P. Nechiporuk T. Pulst S.M. 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Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate.Neurogenetics. 2015; 16: 181-192Crossref PubMed Scopus (48) Google Scholar) by Lsm and Lsm-AD sequences that mediate the association with RNAs (9Satterfield T.F. Pallanck L.J. Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with polyribosomes.Hum. Mol. Genet. 2006; 15: 2523-2532Crossref PubMed Scopus (144) Google Scholar, 10Yokoshi M. Li Q. Yamamoto M. Okada H. Suzuki Y. Kawahara Y. Direct binding of Ataxin-2 to distinct elements in 3′ UTRs promotes mRNA stability and protein expression.Mol. Cell. 2014; 55: 186-198Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 11Castello A. Fischer B. Eichelbaum K. Horos R. Beckmann B.M. Strein C. Davey N.E. Humphreys D.T. Preiss T. Steinmetz L.M. Krijgsveld J. Hentze M.W. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.Cell. 2012; 149: 1393-1406Abstract Full Text Full Text PDF PubMed Scopus (1353) Google Scholar). ATXN2 is normally localized at the rough endoplasmic reticulum (12van de Loo S. Eich F. Nonis D. Auburger G. Nowock J. Ataxin-2 associates with rough endoplasmic reticulum.Exp. Neurol. 2009; 215: 110-118Crossref PubMed Scopus (63) Google Scholar), but it relocalizes during periods of low cell energy together with PABPC1 to stress granules where the quality control of RNA occurs (3Nonhoff U. Ralser M. Welzel F. Piccini I. Balzereit D. Yaspo M.L. Lehrach H. Krobitsch S. Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules.Mol. Biol. Cell. 2007; 18: 1385-1396Crossref PubMed Scopus (252) Google Scholar) and where fasting responses are modulated (13Heck M.V. Azizov M. Stehning T. Walter M. Kedersha N. Auburger G. 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Thus, the elucidation of the molecular effects of ATXN2 deficiency and of the physiological roles of Ataxin-2 may help to design neuroprotective approaches that are novel. Hence, we chose to document the global proteomic and metabolomic profile of Atxn2-KO mice in crucial tissues affected by Ataxin-2 loss- and gain-of-function, the liver and the cerebellum, respectively. This effort m" @default.
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• W2257662942 date "2016-05-01" @default.
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• W2257662942 title "Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations" @default.
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