α-Synuclein gene deletion decreases brain palmitate uptake and alters the palmitate metabolism in the absence of α-synuclein palmitate binding
α-Synuclein gene deletion decreases brain palmitate uptake and alters the palmitate metabolism in the absence of α-synuclein palmitate binding
复制标题
DOI：
10.1021/bi0502137
复制
发表时间：
2005-06-14
期刊：
影响因子：
2.9
通讯作者：
Murphy, EJ
中科院分区：
文献类型：
--
作者：
Golovko, MY;Faergeman, NJ;Murphy, EJ
α-突触核蛋白是中枢神经系统中丰富的蛋白质，其与许多神经退行性疾病（包括帕金森病）相关。其生理功能知之甚少，尽管最近有人提出其作为脂肪酸结合蛋白发挥作用。为了更好地确定α-突触核蛋白在脑脂肪酸摄取和代谢中的作用，我们用[1-C-14]棕榈酸（16：0）输注清醒的野生型或α-突触核蛋白基因消除的小鼠，并评估脑磷脂中的脂肪酸摄取和周转动力学。α-突触核蛋白缺乏使脑16：0摄取降低35%，并降低其对有机部分的靶向。在α-突触核蛋白基因消融的小鼠中，进入脑酰基辅酶A池的16：0的掺入系数显著降低36%。由于掺入系数本身不能预测单个磷脂类别中的脂肪酸周转率，因此我们计算了16：0进入脑磷脂池的动力学值。α-突触核蛋白缺乏降低了许多磷脂类的掺入率和16：0的部分周转率，但也增加了胆碱甘油磷脂的掺入率和16：0的部分周转率。在肝磷脂中未观察到掺入率或周转率差异，证实这些脂质代谢变化具有脑特异性。使用滴定微量热法，我们观察到16：0或油酸在体外没有结合到α-突触核蛋白。因此，α-突触核蛋白对16：0摄取和代谢的影响与FABP相似，但与FABP不同的是，它不直接结合16：0;因此，这些作用的机制与经典FABP不同。
alpha-Synuclein is an abundant protein in the central nervous system that is associated with a number of neurodegenerative disorders, including Parkinson's disease. Its physiological function is poorly understood, although recently it was proposed to function as a fatty acid binding protein. To better define a role for alpha-synuclein in brain fatty acid uptake and metabolism, we infused awake, wild-type, or alpha-synuclein gene-ablated mice with [1-C-14]palmitic acid (16:0) and assessed fatty acid uptake and turnover kinetics in brain phospholipids. alpha-Synuclein deficiency decreased brain 16:0 uptake 35% and reduced its targeting to the organic fraction. The incorporation coefficient for 16:0 entering the brain acyl-CoA pool was significantly decreased 36% in alpha-synuclein gene-ablated mice. Because incorporation coefficients alone are not predictive of fatty acid turnover in individual phospholipid classes, we calculated kinetic values for 16:0 entering brain phospholipid pools. alpha-Synuclein deficiency decreased the incorporation rate and fractional turnover of 16:0 in a number of phospholipid classes, but also increased the incorporation rate and fractional turnover of 16:0 in the choline glycerophospholipids. No differences in incorporation rate or turnover were observed in liver phospholipids, confirming that these changes in lipid metabolism were brain specific. Using titration microcalorimetry, we observed no binding of 16:0 or oleic acid to alpha-synuclein in vitro. Thus, alpha-synuclein has effects on 16:0 uptake and metabolism similar to those of an FABP, but unlike FABP, it does not directly bind 16:0; hence, the mechanism underlying these effects is different from that of a classical FABP.