Higashi Shinji, Biskup Saskia, West Andrew B, Trinkaus Daniel, Dawson Valina L, Faull Richard L M, Waldvogel Henry J, Arai Heii, Dawson Ted M, Moore Darren J, Emson Piers C
Laboratory of Molecular Neuroscience, The Babraham Institute, Babraham, Cambridge, UK.
Brain Res. 2007 Jun 25;1155:208-19. doi: 10.1016/j.brainres.2007.04.034. Epub 2007 Apr 19.
Mutations in the LRRK2 gene cause autosomal dominant, late-onset parkinsonism, which presents with pleomorphic pathology including alpha-synucleopathy. To promote our understanding of the biological role of LRRK2 in the brain we examined the distribution of LRRK2 mRNA and protein in postmortem human brain tissue from normal and neuropathological subjects. In situ hybridization and immunohistochemical analysis demonstrate the expression and localization of LRRK2 to various neuronal populations in brain regions implicated in Parkinson's disease (PD) including the cerebral cortex, caudate-putamen and substantia nigra pars compacta. Immunofluorescent double labeling studies additionally reveal the prominent localization of LRRK2 to cholinergic-, calretinin- and GABA(B) receptor 1-positive, dopamine-innervated, neuronal subtypes in the caudate-putamen. The distribution of LRRK2 in brain tissue from sporadic PD and dementia with Lewy bodies (DLB) subjects was also examined. In PD brains, LRRK2 immunoreactivity localized to nigral neuronal processes is dramatically reduced which reflects the disease-associated loss of dopaminergic neurons in this region. However, surviving nigral neurons occasionally exhibit LRRK2 immunostaining of the halo structure of Lewy bodies. Moreover, LRRK2 immunoreactivity is not associated with Lewy neurites or with cortical Lewy bodies in sporadic PD and DLB brains. These observations indicate that LRRK2 is not a primary component of Lewy bodies and does not co-localize with mature fibrillar alpha-synuclein to a significant extent. The localization of LRRK2 to key neuronal populations throughout the nigrostriatal dopaminergic pathway is consistent with the involvement of LRRK2 in the molecular pathogenesis of familial and sporadic parkinsonism.
LRRK2基因的突变会导致常染色体显性遗传的迟发性帕金森症，其呈现出多形性病理特征，包括α-突触核蛋白病。为了增进我们对LRRK2在大脑中的生物学作用的理解，我们检测了正常和神经病理学受试者死后大脑组织中LRRK2 mRNA和蛋白质的分布。原位杂交和免疫组织化学分析表明，LRRK2在帕金森病（PD）相关脑区的各种神经元群体中表达并定位，这些脑区包括大脑皮层、尾状核-壳核和黑质致密部。免疫荧光双标记研究还揭示了LRRK2在尾状核-壳核中胆碱能、钙视网膜蛋白和GABA(B)受体1阳性、多巴胺能支配的神经元亚型中显著定位。我们还检测了散发性PD和路易体痴呆（DLB）受试者脑组织中LRRK2的分布。在PD大脑中，定位于黑质神经元突起的LRRK2免疫反应性显著降低，这反映了该区域与疾病相关的多巴胺能神经元的丧失。然而，存活的黑质神经元偶尔会表现出路易小体晕环结构的LRRK2免疫染色。此外，在散发性PD和DLB大脑中，LRRK2免疫反应性与路易神经突或皮质路易小体无关。这些观察结果表明，LRRK2不是路易小体的主要成分，并且在很大程度上不与成熟的纤维状α-突触核蛋白共定位。LRRK2在整个黑质纹状体多巴胺能通路的关键神经元群体中的定位与LRRK2参与家族性和散发性帕金森症的分子发病机制一致。
