Update on the genetics of Parkinson's disease
Update on the genetics of Parkinson's disease
复制标题
DOI：
10.1002/mds.21676
复制
发表时间：
2007-01-01
影响因子：
8.6
通讯作者：
Gasser, Thomas
中科院分区：
文献类型：
--
作者：
Gasser, Thomas
在过去的几年中，一些单基因形式的帕金森病（PD）的基因已经被定位和/或克隆。在罕见的显性PD家族中发现了α -突触核蛋白基因突变，表明该蛋白在路易小体中的聚集可能是该疾病分子发病机制的关键步骤。最近发现了显性PD的一个更常见的原因，即富亮氨酸重复激酶2 （LRRK2）基因突变。帕金森基因、DJ-1和PINK1的突变都可导致常染色体隐性帕金森病的早期发病。这些基因与蛋白酶体蛋白降解途径、氧化应激反应和线粒体功能有关。隐性基因的突变可能是通过功能丧失机制致病的，这表明它们的野生型产物保护多巴胺能细胞免受各种损害。有证据表明，至少这些基因中的一些可能在常见散发性帕金森病的病因学中起直接作用。此外，在罕见的单基因变异中发现的细胞通路可能也揭示了典型散发性帕金森病的分子发病机制。(C) 2007运动障碍学会
Over the last few years, several genes for monogenic forms of Parkinson's disease (PD) have been mapped and/or cloned. Mutations have been identified in the gene for alpha-synuclein in rare families with dominant PD, indicating that aggregation of this protein in Lewy bodies is probably a crucial step in the molecular pathogenesis of the disorder. A much more common cause for dominant PD, mutations in the gene for leucine-rich repeat kinase 2 (LRRK2), has recently been identified. Mutations in the parkin gene, in DJ-1 and PINK1 all cause autosomal recessive parkinsonism of early onset. These genes have been implicated in the proteasomal protein degradation pathway, in the oxidative stress response and mitochondrial function. Mutations in recessive genes probably are pathogenic through loss-of-function mechanisms, suggesting that their wildtype products protect dopaminergic cells against a variety of insults. Evidence is emerging that at least some of these genes may play a direct role in the etiology of the common sporadic form of PD. Further, it is likely that the cellular pathways identified in rare monogenic variants of the disease also shed light on the molecular pathogenesis in typical sporadic PD. (C) 2007 Movement Disorder Society