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

单基因缺陷家族性帕金森病的存在支持了遗传因素在帕金森病发病机制中的作用。最近，一些遗传型帕金森病的基因已被定位和/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性家族性帕金森病，具有多巴反应性帕金森综合征特征和路易体阳性病理。相反，常染色体隐性遗传性青少年帕金森综合症(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，该基因编码的蛋白在N端部分与泛素有部分同源性，并有两个RNG指状动机与IBR(中间环)。到目前为止，已经发现了包括外显子重排和点突变在内的各种突变。此外，PAL-KIN定位于高尔基复合体，提示PAL-KIN可能参与轴突运输系统。最近，我们发现Parkin与泛素结合酶E2相互作用，并作为泛素-蛋白连接酶E3与Ub-蛋白酶体途径功能相连。这些特征缺乏路易小体，这被认为是病理特征。我们的发现将加强对神经元死亡机制的探索，以及观察到可变包涵体的其他神经退行性疾病。

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.