LRRK2 in Parkinson's disease and dementia with Lewy bodies.
LRRK2 in Parkinson's disease and dementia with Lewy bodies.
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LRRK2在帕金森氏病和痴呆症患有路易尸体中。
DOI：
10.1186/1750-1326-1-17
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发表时间：
2006-11-30
影响因子：
15.1
通讯作者：
Chen, Shu G.
中科院分区：
文献类型：
--
作者：
Zhu, Xiongwei;Babar, Asim;Siedlak, Sandra L.;Yang, Qiwei;Ito, Genta;Iwatsubo, Takeshi;Smith, Mark A.;Perry, George;Chen, Shu G.
到目前为止，编码富含亮氨酸的重复蛋白激酶2的LRRK2突变是与常染色体显性遗传和特发性帕金森病(PD)相关的最常见的遗传原因。为了检验LRRK2是否与帕金森病和其他相关疾病的神经病理直接相关，我们使用高度特异的LRRK2抗体分析了受帕金森病和路易体痴呆(DLB)影响的患者大脑中的LRRK2。我们证明，抗LRRK2抗体强烈标记脑干和皮质路易小体，分别是帕金森病和德鲁伊氏病的病理特征。此外，抗LRRK2还标记了脑血管、轴突和神经元胞体。有趣的是，LRRK2的免疫细胞化学图谱随着不同抗体的不同而不同，这取决于沿着LRRK2蛋白的特定抗原位置。所有针对LRRK2不同区域的抗LRRK2抗体在Western blotts上均与重组LRRK2呈免疫反应。然而，只有针对LRRK2的N-末端和C-末端的抗体，而不是含有折叠蛋白结构域的区域，在路易小体的免疫标记中呈阳性，这表明LRRK2的特定抗原部位在组织切片上有不同的暴露。我们认为LRRK2在PD和DLB中都是路易体的组成部分，因此在路易体的形成和疾病的发病机制中起着重要的作用。了解LRRK2在正常和病理条件下的细胞定位将加深我们对其功能和与帕金森病及相关疾病进展相关的分子通路的理解。
Mutations in LRRK2 encoding leucine-rich repeat kinase 2 are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic Parkinson's disease (PD). To examine whether LRRK2 is directly associated with neuropathology of PD and other related disorders, we analyzed LRRK2 in brains of patients affected by PD and dementia with Lewy bodies (DLB) using highly specific antibodies to LRRK2. We demonstrated that anti-LRRK2 antibodies strongly labelled brainstem and cortical Lewy bodies, the pathological hallmarks of PD and DLB, respectively. In addition, anti-LRRK2 also labelled brain vasculature, axons, and neuronal cell bodies. Interestingly, the immunocytochemical profile of LRRK2 varied with different antibodies depending upon specific antigenic sites along the LRRK2 protein. All anti-LRRK2 antibodies tested that were raised against various regions of LRRK2, were found to be immunoreactive to recombinant LRRK2 on Western blots. However, only the antibodies raised against the N-terminal and C-terminal regions of LRRK2, but not the regions containing folded protein domains, were positive in immunolabeling of Lewy bodies, suggesting a differential exposure of specific antigenic sites of LRRK2 on tissue sections. We conclude that LRRK2 is a component of Lewy bodies in both PD and DLB, and therefore plays an important role in the Lewy body formation and disease pathogenesis. Information on the cellular localization of LRRK2 under normal and pathological conditions will deepen our understanding of its functions and molecular pathways relevant to the progression of PD and related disorders.
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影响因子：
2.2
作者：
Mata, IF;Kachergus, JM;Farrer, MJ
通讯作者：
Farrer, MJ
影响因子：
3.3
作者：
Melrose, H;Lincoln, S;Farrer, M
通讯作者：
Farrer, M
影响因子：
21.3
作者：
Fujiwara, H;Hasegawa, M;Iwatsubo, T
通讯作者：
Iwatsubo, T
影响因子：
11.2
作者：
Giasson, BI;Covy, JP;Van Deerlin, VM
通讯作者：
Van Deerlin, VM
影响因子：
3.5
作者：
Gloeckner, CJ;Kinkl, N;Ueffing, M
通讯作者：
Ueffing, M