Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations
Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations
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DOI：
10.1074/mcp.m115.056770
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发表时间：
2016-05-01
影响因子：
7
通讯作者：
Auburger, Georg
中科院分区：
文献类型：
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作者：
Meierhofer, David;Halbach, Melanie;Auburger, Georg
在全基因组关联研究中，人类Ataxin-2 （ATXN2）基因位点变异与肥胖、1型糖尿病和高血压有关，而小鼠研究表明，ATXN2基因敲除可导致肥胖、胰岛素抵抗和血脂异常。有趣的是，酵母和果蝇中ATXN2蛋白同源物的缺乏可以挽救由TDP-43和Ataxin-1毒性引发的神经变性过程。为了通过无偏方法了解ATXN2缺乏的分子效应，我们使用无标记质谱法定量了ATXN2敲除小鼠的整体蛋白质组和代谢组。在肝组织中，ACADS、ALDH6A1、ALDH7A1、IVD、MCCC2、PCCA、OTC蛋白显著下调，支链及其他氨基酸代谢、脂肪酸、柠檬酸循环下调通路生物信息学富集。小脑蛋白质组学和代谢组学的统计趋势支持了这些发现。他们与最近的说法一致，即PBP1， ATXN2的酵母同源物，在细胞应激期间隔离营养传感器TORC1。总的来说，ATXN2似乎调节营养和代谢，其活性变化是生长过度或细胞萎缩的决定因素。
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.