Hattori N, Shimura H, Kubo S, Suzuki T, Tanaka K, Mizuno Y
Dept. of Neurology, Juntendo Univ. School of Med., Tokyo 113-0033, Japan.
Rinsho Shinkeigaku. 2000 Dec;40(12):1293-6.
The contribution of genetic factors in the pathogenesis of PD is supported by the demonstration of the high concordance in twins studies using PET, the increased risk among relatives of PD patients in case control and family studies, and the existence of familial PD and parkinsonism by single gene defect. Recently, two genes such as alpha-synuclein and parkin have been identified. alpha-Synuclein is involved in a rare dominant form of familial PD with dopa responsive parkinsonian features and Lewy body positive pathology. In contrast, parkin is responsible for autosomal recessive form (AR-JP) of early onset PD with Lewy body-negative pathology. To date, variable mutations such as deletions or point mutations have been reported in AR-JP patients from world wide. In addition, the localization of parkin indicates parkin may are involved in the axonal transport system. More recently, we have found that parkin interacts with ubiquitin-conjugating enzyme, UbcH 7, and is functionally linked to the ubiquitin-proteasome pathway as a ubiquitin ligase. These findings fit the characteristics of lack of Lewy bodies which are cytoplasmic inclusions considered a pathological hallmark. Our findings should enhance the exploration of the mechanisms of neuronal death in PD as well as other neurodegenerative disorders of which variable inclusion bodies are observed.
帕金森病（PD）发病机制中遗传因素的作用得到了多项研究的支持，包括使用正电子发射断层扫描（PET）的双胞胎研究显示出的高一致性、病例对照研究和家族研究中PD患者亲属患病风险的增加，以及单基因缺陷导致的家族性PD和帕金森综合征的存在。最近，已经鉴定出两个基因，如α-突触核蛋白和帕金森蛋白。α-突触核蛋白与一种罕见的显性家族性PD有关，具有多巴反应性帕金森特征和路易体阳性病理改变。相比之下，帕金森蛋白则导致早发性PD的常染色体隐性形式（AR-JP），伴有路易体阴性病理改变。迄今为止，世界各地的AR-JP患者中已报道了多种突变，如缺失或点突变。此外，帕金森蛋白的定位表明它可能参与轴突运输系统。最近，我们发现帕金森蛋白与泛素结合酶UbcH 7相互作用，并作为泛素连接酶在功能上与泛素-蛋白酶体途径相关联。这些发现符合缺乏路易体的特征，路易体是被认为是病理标志的细胞质内含物。我们的发现应能加强对PD以及其他观察到各种包涵体的神经退行性疾病中神经元死亡机制的探索。
