Mutational and functional analysis for Familial Parkinson's disease

帕金森病（PD）是第二常见的神经退行性疾病，在65岁以上的人群中患病率为1%。虽然大多数PD病例是散发的，但现在很清楚遗传因素有助于PD的发病机制。在本研究中，我们发现了PINK 1中的几个突变，负责PARK 6。隐性遗传者约<9%。此外，另一个致病基因DJ-1已被鉴定为PARK 7的致病基因。但是，我们没有发现DJ-1突变。结合parkin基因突变分析，我们研究的患者中约有40%在报告的基因中没有突变。因此，我们认为可能存在未知基因的新突变。现在，我们继续进行连锁研究，以确定一个新的基因。相反，对基因产物的功能分析可以为我们阐明单基因PD和散发性PD的发病机制提供很好的信息。在本研究中，我们发现了a-突触核蛋白和parkin之间的共同途径，如多巴胺代谢。利用反义parkin链可以建立体外敲低parkin基因的方法。敲除parkin可诱导由多巴胺醌衍生的多巴胺Chrome的增加。有趣的是，这种增加被α-突触核蛋白的表达所抑制。此外，parkin相互作用分子14-3-3η抑制parkin连接酶的活性。通过表达α-突触核蛋白恢复该系统。总之，PARK 1和PARK 2的基因产物具有共同的途径。研究结果还表明，所有的基因产物在黑质变性的发病机制中具有共同的途径。

Parkinson's disease (PD) is the second most common neurodegenerative disorder with a prevalence of 1% in individuals older than 65 years of age. Although the majority of PD cases are sporadic, it is now clear that genetic factors contribute to the pathogenesis of PD. In the present study, we found several mutations in PINK1, responsible for PARK6. Approximately <9% among the patients with recessive mode of inheritance. Furthermore, another causative gene, DJ-1 has been identified as a causative gene for PARK7. However, we did not find out DJ-1 mutations. Taken together with parkin gene mutations analysis, approximately 40% of the patients we studied had no mutations in the reported genes. Thus, we believed that a novel mutation in unknown genes could be present. Now we continue to perform the linkage study for identification of a novel gene. In contrast, functional analysis for the gene products could provide us good information for elucidating the mechanism of not only monogenic PD but also sporadic PD. In the present study, we found a common pathway between a-synuclein and parkin such as dopamine metabolisms. We could establish the in vitro assay knock-down parkin using antisense parkin strand. Knock-down parkin induced the increasing of dopamine chrome derived from dopamine quinone. Interestingly, the increasing was inhibited by expression of a-synuclein. In addition, 14-3-3ηthat is one of parkin interaqctive molecules inhibited parkin ligase activities. This system was recovered by expression of a-synuclein. In conclusions, gene products for PARK1 and PARK2 shared common pathways. The findings also indicate that all the gene products share common pathways in the pathogenesis of nigral degeneration.