Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Social Cooperation Program of Brain and Neurological Disorders, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Hum Mol Genet. 2021 Aug 12;30(17):1618-1631. doi: 10.1093/hmg/ddab146.
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson disease. It has been shown that Lrrk2 knockout (KO) rodents have enlarged lamellar bodies (LBs) in their alveolar epithelial type II cells, although the underlying mechanisms remain unclear. Here we performed proteomic analyses on LBs isolated from Lrrk2 KO mice and found that the LB proteome is substantially different in Lrrk2 KO mice compared with wild-type mice. In Lrrk2 KO LBs, several Rab proteins were increased, and subunit proteins of BLOC-1-related complex (BORC) were decreased. The amount of surfactant protein C was significantly decreased in the bronchoalveolar lavage fluid obtained from Lrrk2 KO mice, suggesting that LB exocytosis is impaired in Lrrk2 KO mice. We also found that the enlargement of LBs is recapitulated in A549 cells upon KO of LRRK2 or by treating cells with LRRK2 inhibitors. Using this model, we show that KO of BORCS6, a BORC subunit gene, but not other BORC genes, causes LB enlargement. Our findings implicate the LRRK2-BORCS6 pathway in the maintenance of LB morphology.
富含亮氨酸重复激酶 2（LRRK2）与帕金森病的发病机制有关。已经表明， Lrrk2 敲除（KO）啮齿动物的肺泡上皮 II 型细胞中的板层小体（LB）增大，尽管其潜在机制尚不清楚。在这里，我们对 Lrrk2 KO 小鼠分离的 LB 进行了蛋白质组学分析，发现与野生型小鼠相比，LRRK2 KO 小鼠的 LB 蛋白质组有很大的不同。在 Lrrk2 KO LB 中，几种 Rab 蛋白增加，BLOC-1 相关复合物（BORC）的亚基蛋白减少。从 Lrrk2 KO 小鼠的支气管肺泡灌洗液中获得的表面活性蛋白 C 的量显着减少，表明 Lrrk2 KO 小鼠的 LB 胞吐作用受损。我们还发现，在 A549 细胞中敲除 LRRK2 或用 LRRK2 抑制剂处理细胞后，LB 会增大。使用该模型，我们表明 BORCS6（BORC 亚基基因）的 KO 而不是其他 BORC 基因的 KO 导致 LB 增大。我们的发现表明 LRRK2-BORCS6 途径在维持 LB 形态中起作用。
