Tang Beisha, Xiong Hui, Sun Ping, Zhang Yuhu, Wang Danling, Hu Zhengmao, Zhu Zanhua, Ma Hong, Pan Qian, Xia Jia-Hui, Xia Kun, Zhang Zhuohua
National Laboratory of Medical Genetics, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
Hum Mol Genet. 2006 Jun 1;15(11):1816-25. doi: 10.1093/hmg/ddl104. Epub 2006 Apr 21.
Mutations in genes encoding both DJ-1 and pten-induced kinase 1 (PINK1) are independently linked to autosomal recessive early-onset familial forms of Parkinson's disease (PD). We here report identification of a family with PD patients harboring novel heterozygous missense mutations in both PINK1 and DJ-1 genes encoding DJ-1A39S and PINK1P399L, respectively. In transfected cells, DJ-1 interacts with PINK1. PINK1P399L is less stable than the wild-type protein and is degraded via the ubiquitin-mediated proteasomal pathway. Expression of wild-type DJ-1 increased steady-state levels of PINK1, whereas expression of DJ-1A39S reduced steady-state levels of PINK1. Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP(+))-induced death of dopaminergic SH-SY5Y cells. In contrast, co-expression of PD-associated DJ-1A39S and PINK1P399L significantly potentiated susceptibility of SH-SY5Y cells to MPP(+)-induced cell death. This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.
编码DJ-1和磷酸酶与张力蛋白同源物诱导激酶1（PINK1）的基因突变分别与常染色体隐性遗传的早发性家族性帕金森病（PD）独立相关。我们在此报告了一个帕金森病患者家族，其携带分别编码DJ-1A39S和PINK1P399L的PINK1和DJ-1基因中的新型杂合错义突变。在转染细胞中，DJ-1与PINK1相互作用。PINK1P399L比野生型蛋白更不稳定，并通过泛素介导的蛋白酶体途径降解。野生型DJ-1的表达增加了PINK1的稳态水平，而DJ-1A39S的表达降低了PINK1的稳态水平。此外，野生型DJ-1和PINK1的共表达抑制了神经毒素1-甲基-4-苯基吡啶鎓（MPP(+)）诱导的多巴胺能SH-SY5Y细胞死亡。相反，帕金森病相关的DJ-1A39S和PINK1P399L的共表达显著增强了SH-SY5Y细胞对MPP(+)诱导的细胞死亡的易感性。本研究报告了首例双基因遗传的常染色体隐性帕金森病病例，并证明DJ-1和PINK1通过形成复合物在物理上相互关联并协同作用以保护细胞免受应激。
