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.

Fig. 1.

Volcano plot featuring liver proteome data, with the mean difference of LFQ intensities between Atxn2 KO and WT tissues on the x axis versus statistical significance on the y axis (-log10 of the p value). Significant regulated proteins are identified in red.

Fig. 2.

Log₂ LFQ ion intensities of all six biological replicates in Atxn2-KO/WT liver tissues are shown. Red = KO; blue = WT. Error bars are mean values with S.D.

Fig. 3.

STRING PPI network and pathway analysis of proteins with downregulation at least one standard deviations from the log₂ transformed median values (0.03227 ± 0.4819) in Atxn2-KO/WT liver tissue. Highlighted in red are proteins which belong to the KEGG pathway BCAA. Unconnected nodes were removed.

Fig. 4.

Metabolomics and proteomics overview of the impact of an Atxn2-KO in liver tissue. Indicated are the fold changes of detected proteins and metabolites in KO/WT.