Verwaest Kim A, Vu Trung N, Laukens Kris, Clemens Laura E, Nguyen Huu P, Van Gasse Bjorn, Martins José C, Van Der Linden Annemie, Dommisse Roger
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
Biochim Biophys Acta. 2011 Nov;1812(11):1371-9. doi: 10.1016/j.bbadis.2011.08.001. Epub 2011 Aug 16.
Huntington disease (HD) is a hereditary brain disease. Although the causative gene has been found, the exact mechanisms of the pathogenesis are still unknown. Recent investigations point to metabolic and energetic dysfunctions in HD neurons. Both univariate and multivariate analyses were used to compare proton nuclear magnetic resonance spectra of serum and cerebrospinal fluid (CSF) taken from presymptomatic HD transgenic rats and their wild-type littermates. N-acetylaspartate (NAA), was found to be significantly decreased in the serum of HD rats compared to wild-type littermates. Moreover, in the serum their levels of glutamine, succinic acid, glucose and lactate are significantly increased as well. An increased concentration of lactate and glucose is also found in CSF. There is a 1:1 stoichiometry coupling glucose utilization and glutamate cycling. The observed increase in the glutamine concentration, which indicates a shutdown in the neuronal-glial glutamate-glutamine cycling, results therefore in an increased glucose concentration. The elevated succinic acid concentration might be due to an inhibition of succinate dehydrogenase, an enzyme linked to the mitochondrial respiratory chain and TCA cycle. Moreover, reduced levels of NAA may reflect an impairment of mitochondrial energy production. In addition, the observed difference in lactate supports a deficiency of oxidative energy metabolism in rats transgenic for HD as well. The observed metabolic alterations seem to be more profound in serum than in CSF in presymptomatic rats. All findings suggest that even in presymptomatic rats, a defect in energy metabolism is already apparent. These results support the hypothesis of mitochondrial energy dysfunction in HD.
亨廷顿舞蹈症（HD）是一种遗传性脑部疾病。尽管致病基因已被发现，但其发病的确切机制仍不清楚。最近的研究表明HD神经元存在代谢和能量功能障碍。采用单变量和多变量分析方法，比较了症状前HD转基因大鼠及其野生型同窝仔鼠血清和脑脊液（CSF）的质子核磁共振波谱。结果发现，与野生型同窝仔鼠相比，HD大鼠血清中的N-乙酰天门冬氨酸（NAA）显著降低。此外，在血清中，它们的谷氨酰胺、琥珀酸、葡萄糖和乳酸水平也显著升高。脑脊液中乳酸和葡萄糖的浓度也有所增加。葡萄糖利用和谷氨酸循环存在1:1的化学计量耦合关系。观察到的谷氨酰胺浓度增加表明神经元-胶质细胞谷氨酸-谷氨酰胺循环中断，因此导致葡萄糖浓度升高。琥珀酸浓度升高可能是由于琥珀酸脱氢酶受到抑制，该酶与线粒体呼吸链和三羧酸循环有关。此外，NAA水平降低可能反映线粒体能量产生受损。此外，观察到的乳酸差异也支持HD转基因大鼠存在氧化能量代谢缺陷。在症状前大鼠中，观察到的代谢改变在血清中似乎比在脑脊液中更明显。所有研究结果表明，即使在症状前大鼠中，能量代谢缺陷也已明显。这些结果支持了HD中线粒体能量功能障碍的假说。
