Liot Géraldine, Valette Julien, Pépin Jérémy, Flament Julien, Brouillet Emmanuel
CEA, DRF, I(2)BM, Molecular Imaging Research Center (MIRCen), F-92265, Fontenay-aux-Roses, France; CEA, CNRS, Paris-Sud University, Paris-Saclay University, UMR9199, Neurodegenerative Diseases Laboratory, F-92265, Fontenay-aux-Roses, France.
CEA, DRF, I(2)BM, Molecular Imaging Research Center (MIRCen), F-92265, Fontenay-aux-Roses, France; Institut National de la santé et de la recherche médicale (Inserm), UMS 27, F-92265, Fontenay-aux-Roses, France.
Biochem Biophys Res Commun. 2017 Feb 19;483(4):1084-1095. doi: 10.1016/j.bbrc.2016.09.065. Epub 2016 Sep 14.
Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The most striking neuropathological change in HD is the early atrophy of the striatum. While the disease progresses, other brain structures also degenerate, including the cerebral cortex. Changes are also seen outside the brain, in particular weight loss/cachexia despite high dietary intake. The disease is caused by an abnormal expansion of a CAG repeat in the gene encoding the huntingtin protein (Htt). This mutation leads to the expression of a poly-glutamine stretch that changes the biological functions of mutant Htt (mHtt). The mechanisms underlying neurodegeneration in HD are not totally elucidated. Here, we discuss recent results obtained in patients, animal and cellular models suggesting that early disturbance in energy metabolism at least in part associated with mitochondrial defects may play a central role, even though all data are not congruent, possibly because most findings were obtained in cell culture systems or using biochemical analyses of post mortem tissues from rodent models. Thus, we put a particular focus on brain imaging studies that could identify biomarkers of energy defects in vivo and would be of prime interest in preclinical and clinical trials testing the efficacy of new therapies targeting energy metabolism in HD.
亨廷顿舞蹈症（HD）是一种遗传性进行性神经退行性疾病，与非自主性异常运动（舞蹈症）、认知缺陷及精神障碍有关。HD最显著的神经病理学变化是纹状体早期萎缩。随着疾病进展，其他脑结构也会退化，包括大脑皮层。脑外也会出现变化，尤其是尽管饮食摄入量高但仍会出现体重减轻/恶病质。该疾病由编码亨廷顿蛋白（Htt）的基因中CAG重复序列异常扩增引起。这种突变导致多聚谷氨酰胺序列的表达，从而改变突变型Htt（mHtt）的生物学功能。HD神经退行性变的潜在机制尚未完全阐明。在此，我们讨论在患者、动物和细胞模型中获得的最新结果，这些结果表明能量代谢的早期紊乱至少部分与线粒体缺陷相关，可能起着核心作用，尽管所有数据并不一致，这可能是因为大多数研究结果是在细胞培养系统中获得的，或是使用来自啮齿动物模型的死后组织进行生化分析得到的。因此，我们特别关注脑成像研究，这些研究能够识别体内能量缺陷的生物标志物，并且在测试针对HD能量代谢的新疗法疗效的临床前和临床试验中具有重要意义。
