Perry George, Zhu Xiongwei, Babar Asim K, Siedlak Sandra L, Yang Qiwei, Ito Genta, Iwatsubo Takeshi, Smith Mark A, Chen Shu G
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
Neurodegener Dis. 2008;5(3-4):222-4. doi: 10.1159/000113708. Epub 2008 Mar 6.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic Parkinson's disease.
To examine whether LRRK2 is directly associated with the pathological structures of Parkinson's disease, dementia with Lewy bodies, and other related disorders using highly specific antibodies to LRRK2.
LRRK2 antibodies strongly labeled brainstem and cortical Lewy bodies, the pathological hallmarks of Parkinson's disease and dementia with Lewy bodies, respectively. We found that 20-100% (mean 60%) of alpha-synuclein-positive Lewy bodies contained LRRK2. While antibodies raised against various regions of LRRK2 were previously shown to label recombinant LRRK2 on Western blots, only antibodies raised against the N- and C-termini, but not the regions containing folded protein domains of LRRK2, immunolabeled Lewy bodies. In Alzheimer's disease, Hirano bodies were found to contain LRRK2 and the neurofibrillary tangles in progressive supranuclear palsy remained unlabeled.
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 Parkinson's disease and related disorders.
富含亮氨酸重复激酶2（LRRK2）的突变是迄今为止与常染色体显性和特发性帕金森病相关的最常见遗传病因。
使用针对LRRK2的高特异性抗体，研究LRRK2是否与帕金森病、路易体痴呆及其他相关疾病的病理结构直接相关。
LRRK2抗体分别强烈标记了帕金森病和路易体痴呆的病理特征——脑干和皮质路易体。我们发现，20%至100%（平均60%）的α-突触核蛋白阳性路易体含有LRRK2。虽然先前已证明针对LRRK2不同区域产生的抗体可在蛋白质免疫印迹法中标记重组LRRK2，但只有针对N端和C端产生的抗体，而非针对含有LRRK2折叠蛋白结构域区域产生的抗体，能对路易体进行免疫标记。在阿尔茨海默病中，发现 Hirano小体含有LRRK2，而进行性核上性麻痹中的神经原纤维缠结未被标记。
关于LRRK2在正常和病理条件下细胞定位的信息，将加深我们对其与帕金森病及相关疾病进展有关的功能和分子途径的理解。
