Inoshita Tsuyoshi, Liu Jun-Yi, Taniguchi Daisuke, Ishii Ryota, Shiba-Fukushima Kahori, Hattori Nobutaka, Imai Yuzuru
Department of Neurodegenerative and Demented Disorders, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Department of Neurology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
iScience. 2022 Nov 2;25(12):105476. doi: 10.1016/j.isci.2022.105476. eCollection 2022 Dec 22.
Some Parkinson's disease (PD)-causative/risk genes, including the PD-associated kinase leucine-rich repeat kinase 2 (LRRK2), are involved in membrane dynamics. Although LRRK2 and other PD-associated genes are believed to regulate synaptic functions, axonal transport, and endolysosomal activity, it remains unclear whether a common pathological pathway exists. Here, we report that the loss of Lrrk, an ortholog of human LRRK2, leads to the accumulation of the lysosome-related organelle regulator, Arl8 along with dense core vesicles at the most distal boutons of the neuron terminals in . Moreover, the inactivation of a small GTPase Rab3 and altered Auxilin activity phenocopied Arl8 accumulation. The accumulation of Arl8-positive vesicles is UNC-104-dependent and modulated by PD-associated genes, Auxilin, VPS35, RME-8, and INPP5F, indicating that VPS35, RME-8, and INPP5F are upstream regulators of Lrrk. These results indicate that certain PD-related genes, along with LRRK2, drive precise neuroaxonal transport of dense core vesicles.
一些帕金森病（PD）致病/风险基因，包括与PD相关的激酶富含亮氨酸重复激酶2（LRRK2），都参与膜动力学过程。尽管LRRK2和其他与PD相关的基因被认为可调节突触功能、轴突运输和内溶酶体活性，但目前尚不清楚是否存在共同的病理途径。在此，我们报告称，人类LRRK2的直系同源基因Lrrk缺失会导致溶酶体相关细胞器调节因子Arl8以及致密核心囊泡在神经元末端最远端的轴突终扣处积累。此外，小GTP酶Rab3的失活和辅助蛋白活性的改变模拟了Arl8的积累。Arl8阳性囊泡的积累依赖于UNC-104，并受与PD相关的基因、辅助蛋白、VPS35、RME-8和INPP5F的调节，这表明VPS35、RME-8和INPP5F是Lrrk的上游调节因子。这些结果表明，某些与PD相关的基因与LRRK2一起驱动致密核心囊泡的精确神经轴突运输。
