Abnormal localization of leucine-rich repeat kinase 2 to the endosomal-lysosomal compartment in lewy body disease.
Abnormal localization of leucine-rich repeat kinase 2 to the endosomal-lysosomal compartment in lewy body disease.
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DOI：
10.1097/nen.0b013e3181b44ed8
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发表时间：
2009-09
影响因子：
3.2
通讯作者：
Iseki E
中科院分区：
文献类型：
--
作者：
Higashi S;Moore DJ;Yamamoto R;Minegishi M;Sato K;Togo T;Katsuse O;Uchikado H;Furukawa Y;Hino H;Kosaka K;Emson PC;Wada K;Dawson VL;Dawson TM;Arai H;Iseki E
富亮氨酸重复激酶2 （LRRK2）基因的错义突变是家族性和散发性帕金森病（PD）的最常见原因，也与多种病理改变有关。LRRK2突变导致这些病理表型的机制尚不清楚。我们使用3种不同的抗LRRK2抗体的免疫组织化学方法来表征LRRK2在21名患有各种神经退行性疾病的受试者和7名对照组中的表达。LRRK2免疫反应性局限于脑干型路易小体（LBs）的一部分，而不局限于皮质型路易小体、tau阳性包涵体或TAR-DNA结合蛋白43阳性包涵体。在PD或痴呆伴路易体（DLB）患者中，LRRK2免疫反应性常表现为受累脑区神经元内增大的颗粒或空泡，包括黑质、杏仁核和内嗅皮质。DLB脑内嗅皮质神经元中lrrk2阳性颗粒结构的体积与对照组相比显著增加（p<0.05）。双重免疫标记表明，这些lrrk2阳性颗粒结构经常与内体晚期标记物Rab7B共定位，偶尔与溶酶体标记物LAMP2共定位。这些结果表明，在神经退行性疾病中，特别是在LB疾病患者的大脑中，LRRK2通常定位于形态学改变的神经元内的核内体-溶酶体隔室。
Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common causes of both familial and sporadic forms of Parkinson disease (PD) and are also associated with a diverse pathological alterations. The mechanisms whereby LRRK2 mutations cause these pathological phenotypes are unknown. We employed immunohistochemistry with 3 distinct anti-LRRK2 antibodies to characterize the expression of LRRK2 in the brains of 21 subjects with various neurodegenerative disorders and 7 controls. LRRK2 immunoreactivity was localized in a subset of brainstem-type Lewy bodies (LBs) but not in cortical-type LBs, tau-positive inclusions or TAR-DNA binding protein-43-positive inclusions. LRRK2 immunoreactivity frequently appeared as enlarged granules or vacuoles within neurons of affected brain regions, including the substantia nigra, amygdala and entorhinal cortex in patients with PD or dementia with Lewy bodies (DLB). The volumes of LRRK2-positive granular structures in neurons of the entorhinal cortex were significantly increased in DLB brains compared to aged-matched control brains (p<0.05). Double immunolabeling demonstrated that these LRRK2-positive granular structures frequently colocalized with the late-endosomal marker Rab7B and occasionally with the lysosomal marker, LAMP2. These results suggest that LRRK2 normally localizes to the endosomal-lysosomal compartment within morphologically altered neurons in neurodegenerative diseases, particularly in the brains of patients with LB diseases.