Bhadra Ankan Kumar, Roy Ipsita
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S., Nagar, Punjab, 160 062, India.
Mol Neurobiol. 2016 Aug;53(6):3900-3913. doi: 10.1007/s12035-015-9329-5. Epub 2015 Jul 12.
A significant correlation has been observed between the length of the polyglutamine tract in huntingtin, its aggregation and the progression of Huntington's disease (HD). The chaperonin TRiC is a potent antagonist of aggregation of mutant huntingtin. Using the well-validated Saccharomyces cerevisiae model of HD, we have investigated the role of age-related post-translational modifications of this heterooligomeric chaperonin on its ability to inhibit aggregation of the mutant protein. We show that the glycerol synthetic enzyme Gpd1 is involved in the post-translational modification of Tcp-1 (subunit of TRiC) by acetylation and glycation through the NAD(+)/NADH shuttle and the triose phosphate intermediate dihydroxyacetone phosphate, respectively. The extent of modification of Tcp-1 shows a negative correlation with the solubility of mutant huntingtin. The absence of Gpd1 also induces heat shock response in yeast cells, further inhibiting aggregation of the mutant protein. Thus, Gpd1 acts as a major regulator of the protein folding machinery in the yeast model of HD. Modification and inactivation of cellular chaperonin are accelerated in an aging cell, which has further deleterious effects for a cell harbouring misfolded/aggregated protein(s).
已观察到亨廷顿蛋白中多聚谷氨酰胺序列的长度与其聚集以及亨廷顿舞蹈症（HD）的病情进展之间存在显著相关性。伴侣蛋白TRiC是突变型亨廷顿蛋白聚集的有效拮抗剂。利用经过充分验证的HD酵母模型，我们研究了这种异源寡聚伴侣蛋白与年龄相关的翻译后修饰对其抑制突变蛋白聚集能力的作用。我们发现甘油合成酶Gpd1分别通过NAD(+)/NADH穿梭途径和磷酸丙糖中间体磷酸二羟丙酮参与Tcp-1（TRiC的亚基）的乙酰化和糖基化翻译后修饰。Tcp-1的修饰程度与突变型亨廷顿蛋白的溶解度呈负相关。Gpd1的缺失还会诱导酵母细胞中的热休克反应，进一步抑制突变蛋白的聚集。因此，在HD酵母模型中，Gpd1是蛋白质折叠机制的主要调节因子。细胞伴侣蛋白的修饰和失活在衰老细胞中加速，这对含有错误折叠/聚集蛋白的细胞具有进一步的有害影响。
