Mutational and functional analyses of the parkin responsible for AR-JP

负责 AR-JP 的 Parkin 的突变和功能分析

• 批准号: 11670641
• 负责人: HATTORI Nobutaka
• 金额: $ 2.5万
• 依托单位: JUNTENDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670641/
• 关键词: AR-JP; Ubiquitin-protein ligase; Young onset Parkinson7s disease; Lewy body; UbcH7; Ubiquitin-proteasome pathway; 家族性パーキンソン病; ユビキチン; RING finger motif

The contribution of genetic factors to the pathogenesis of Parkinson's disease (PD) is supported by the existence of familial PD by single gene defect. Recently, several genes for inherited forms of PD have been mapped and/or identified. α-Synuclein is involved in a rare form of autosomal dominant form of familial PD with doparesponsive parkinsonism features and Lewy body-positive pathology. In contrast, the gene for an autosomal recessive juvenile parkinsonism (AR-JP) was found to be caused by mutations of the pakin gene. AR-JP is the most popular form of early-onset PD.The gene encoded a protein with a partial homology to ubiquitin in the N terminal portion and two RNG-finger like motives with IBR (in-between RINGs). To date, a variety of mutations including exon rearrangements and point mutations have been identified. In addition, pal-kin is localized on the Golgi complex, indicating that parkin may be involved in the axonal transport system. More recently, we have found that parkin interacts with the ubiquitin-conjugating enzyme E2 and is functionally linked to the Ub-proteasome pathway as a ubiquitin-protein ligase, E3. Theses characteristics of a lack of Lewy bodies which are considered to be a pathological hallmark. Our findings should enhance the exploration of the mechanisms of neuronal death as well as other neurodegenerative disorders of which variable inclusion bodies are observed.

遗传因素在帕金森病（PD）发病机制中的作用得到了单基因缺陷家族性PD的存在的支持。最近，遗传形式的PD的几个基因已被映射和/或鉴定。α-突触核蛋白参与了一种罕见的常染色体显性遗传型家族性PD，具有多巴反应性帕金森综合征特征和路易体阳性病理学。相反，常染色体隐性遗传的青少年帕金森综合征（AR-JP）的基因被发现是由pakin基因突变引起的。AR-JP是最常见的早发性PD，该基因编码的蛋白质与泛素部分同源，并具有两个RNG指状结构，与IBR（in-between RINGs）相似。迄今为止，已经鉴定了包括外显子重排和点突变在内的多种突变。此外，帕金是本地化的高尔基复合体，表明帕金可能参与轴突运输系统。最近，我们发现帕金与泛素结合酶E2相互作用，并作为泛素-蛋白连接酶E3与Ub-蛋白酶体途径功能性连接。这些特征缺乏路易体被认为是一个病理标志。我们的研究结果应加强探索神经元死亡的机制，以及其他神经退行性疾病，其中可变包涵体观察。

项目成果

Shimura H, Hattori N, Kubo S, Yoshikawa M, Kitada T, Matsumine H, Asakawa S, Minoshima S, Yamamura Y, Shimizn N, Mizuno Y: "Immunohistochemical and subcellular Jocalization of Parkin : Absence of protein in AR-JP Patients."Ann Neurol. 45. 655-658 (1999)

Shimura H、Hattori N、Kubo S、Yoshikawa M、Kitada T、Matsumine H、Asakawa S、Minoshima S、Yamamura Y、Shimizn N、Mizuno Y：“帕金的免疫组织化学和亚细胞焦化：AR-JP 患者中缺乏蛋白质。

Wang M,Hattori N et al: "Polymarprism in the parkinsone in・・・・・・"Annals of Neurology. 45. 655-658 (1999)

Wang M、Hattori N 等人：“帕金森中的多棱镜……”《神经病学年鉴》45. 655-658 (1999)。

Shimura H. et al.: "Familial parkinson's disease gene product, Parkin, is a ubiquitinprotein ligase"Nature Genet.. 25. 302-305 (2000)

Shimura H.等：“家族性帕金森病基因产物Parkin是一种泛素蛋白连接酶”Nature Genet.. 25. 302-305 (2000)

Hattori N, Shimura H, Kubo S, Wwang M, Shimizu N, Tanaka K, Mizuno Y: "Importance of familial Parkinson's disease and parkinsonism to the understanding of nigral degeneration in sporadic Parkinson's disease."J Neural. Transm. [Suppl] : 60. 85-1000 (2000)

Hattori N、Shimura H、Kubo S、Wwang M、Shimizu N、Tanaka K、Mizuno Y：“家族性帕金森病和帕金森病对于了解散发性帕金森病黑质变性的重要性。”J Neural。

Wang M, Hattori N, Matsumine H, Kobayashi T, Yoshino H, Morioka A, Kitada T, Asakawa S, Minoshima S, Shimizu N, Mizuno Y: "Polymorphism in the parkin gene among sporadic Parkinson's disease."Ann Neurol. 45. 668-672 (1999)

Wang M、Hattori N、Matsumine H、Kobayashi T、Yoshino H、Morioka A、Kitada T、Asakawa S、Minoshima S、Shimizu N、Mizuno Y：“散发性帕金森病中 Parkin 基因的多态性。”Ann Neurol。