Biochemical and pathological characterization of Lrrk2
Biochemical and pathological characterization of Lrrk2
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DOI：
10.1002/ana.20791
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发表时间：
2006-02-01
影响因子：
11.2
通讯作者：
Van Deerlin, VM
中科院分区：
文献类型：
--
作者：
Giasson, BI;Covy, JP;Van Deerlin, VM
目的：富含亮氨酸的重复序列激酶2（LRRK2）的突变最近已被确定为晚发型散发性和家族性帕金森病（PD）的最常见的遗传原因。方法：对尸检病例进行基因分析，确定Lrrk2基因最常见的突变（G2019S）。使用Lrrk2的特异性抗体，对Lrrk2的生化和免疫细胞化学分布进行了评估。确定了3名G2019S Lrrk2突变患者。两名患者表现出典型的PD与路易体，虽然并发的病理变化与阿尔茨海默病也存在于这些人之一。第三个病人的特点是帕金森氏症没有路易体，但表现出营养不良的神经突起在黑质强烈染色的Lrrk2。Lrrk2的积累是唯一的这个病人和Lrrk2没有检测到其他类型的病理性夹杂物。生化分析表明，Lrrk2主要是一个可溶性的约250kDa的细胞质蛋白表达在整个大脑，但也在许多其他orgas.Interpretation的选择性倾向的患者在LRRK2突变发展帕金森综合征的原因尚不清楚，但Lrrk2突变可能总理选择神经元群体的细胞损伤，可导致异常蛋白质聚集。
Objective: Mutations in leucine-rich repeat kinase 2 (LRRK2) recently have been identified as the most common genetic cause of late-onset sporadic and familial Parkinson's disease (PD). The studies herein explore the biological and pathological properties of Lrrk2.Methods: Genetic analysis was per-formed to identify autopsied patients with the most common Lrrk2 mutation (G2019S). Using an antibody specific to Lrrk2, the biochemical and immunocytochemical distribution of Lrrk2 was assessed.Results. Three patients with the G2019S Lrrk2 mutation were identified. Two patients demonstrated classic PD with Lewy bodies, although concurrent pathological changes consistent with Alzheimer's disease were also present in one of these individuals. The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2. Lrrk2 accumulations were unique to this patient and Lrrk2 was not detected in other types of pathological inclusions. Biochemical analysis showed that Lrrk2 is predominantly a soluble approximately 250kDa cytoplasmic protein expressed throughout the brain but also in many other organs.Interpretation The reasons for the selective predisposition of patients with mutations in LRRK2 to develop parkinsonism remains unclear, but Lrrk2 mutations may prime select neuronal populations to cellular insults that can lead to aberrant protein aggregation.