Neuroscience Research, Novartis Institutes for BioMedical Research , Novartis Pharma AG, 4002 Basel, Switzerland.
Sci Rep. 2012;2:262. doi: 10.1038/srep00262. Epub 2012 Feb 13.
Mutations in α-synuclein (αSN) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have been linked to familial Parkinson's disease (PD). Physical and functional interactions between these two proteins have been described. Whether they act additively in vivo to influence disease has remained controversial. αSN is a presynaptic protein and the major constituent of Lewy inclusions, histopathological hallmarks of PD. UCH-L1 regulates ubiquitin stability in the nervous system and its loss results in neurodegeneration in peripheral and central neurons. Here, we used genetics to show that UCH-L1-deficiency together with excess αSN worsen disease. Double mutant mice show earlier-onset motor deficits, a shorter lifespan and forebrain astrogliosis but the additive disease-worsening effects of UCH-L1-deficiency and excess αSN are not accompanied by microgliosis, ubiquitin pathology or changes in pathological αSN protein levels and species.
α-突触核蛋白（αSN）和泛素羧基末端水解酶 L1（UCH-L1）的突变与家族性帕金森病（PD）有关。这两种蛋白质之间存在物理和功能相互作用。它们是否在体内以附加的方式影响疾病一直存在争议。αSN 是一种突触前蛋白，也是路易体的主要成分，路易体是 PD 的组织病理学特征。UCH-L1 调节神经系统中泛素的稳定性，其缺失会导致周围和中枢神经元的神经退行性变。在这里，我们使用遗传学方法表明，UCH-L1 缺陷与过量的 αSN 一起会加重疾病。双突变小鼠表现出运动功能障碍更早出现、寿命更短以及前脑星形胶质细胞增生，但 UCH-L1 缺陷和过量的 αSN 的附加疾病恶化作用并不伴有小胶质细胞增生、泛素病理学改变或病理 αSN 蛋白水平和种类的变化。
