Parkinson disease-associated Leucine-rich repeat kinase regulates UNC-104-dependent axonal transport of Arl8-positive vesicles in Drosophila
Tsuyoshi Inoshita,
Jun-Yi Liu,
Daisuke Taniguchi,
Ryota Ishii,
Kahori Shiba-Fukushima,
Nobutaka Hattori,
Yuzuru Imai
Affiliations
Tsuyoshi Inoshita
Department of Neurodegenerative and Demented Disorders, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Jun-Yi Liu
Department of Neurology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Daisuke Taniguchi
Department of Neurology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Ryota Ishii
Department of Research for Parkinson’s Disease, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Kahori Shiba-Fukushima
Department of Drug Development for Parkinson’s Disease, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Nobutaka Hattori
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; Department of Research for Parkinson’s Disease, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Department of Drug Development for Parkinson’s Disease, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, 2-1-Hirosawa, Wako-shi, Saitama 351-0198, Japan; Corresponding author
Yuzuru Imai
Department of Neurology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Department of Research for Parkinson’s Disease, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Corresponding author
Summary: 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 Drosophila. 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.
