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

doi:10.1016/j.isci.2022.105476

Parkinson disease-associated Leucine-rich repeat kinase regulates UNC-104-dependent axonal transport of Arl8-positive vesicles in Drosophila

iScience. 2022 Nov 2;25(12):105476. doi: 10.1016/j.isci.2022.105476. eCollection 2022 Dec 22.

Authors

Tsuyoshi Inoshita¹, Jun-Yi Liu², Daisuke Taniguchi², Ryota Ishii³, Kahori Shiba-Fukushima⁴, Nobutaka Hattori^{1

2

3

4

5}, Yuzuru Imai^{2

3}

Affiliations

¹ Department of Neurodegenerative and Demented Disorders, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
² Department of Neurology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
³ Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
⁴ Department of Drug Development for Parkinson's Disease, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
⁵ Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, 2-1-Hirosawa, Wako-shi, Saitama 351-0198, Japan.

Abstract

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.

Keywords: Biological sciences; Cell biology; Genetics; Neuroscience.