Department of Biology, Graduate School of Science and Engineering, Chiba University, Inage-ku, Chiba, Japan; Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan
Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan; Division for Development of Autophagy Modulating Drugs, Juntendo University Faculty of Medicine, Tokyo, Japan
Mitsuhiro Kitagawa
Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan
Kentaro Gejima
Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan
Ayami Suzuki
Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan
Hideyuki Saya
Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan; Division of Gene Regulation, Cancer Center, Fujita Health University, Toyoake, Japan
Yasuyuki Kida
Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
Masaya Imoto
Division for Development of Autophagy Modulating Drugs, Juntendo University Faculty of Medicine, Tokyo, Japan
Eisuke Itakura
Department of Biology, Graduate School of Science, Chiba University, Inage-ku, Chiba, Japan
Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan; Division for Development of Autophagy Modulating Drugs, Juntendo University Faculty of Medicine, Tokyo, Japan; Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, Saitama, Japan
Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan; Division for Development of Autophagy Modulating Drugs, Juntendo University Faculty of Medicine, Tokyo, Japan; Department of Neurology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
The autophagy-lysosome pathway plays an indispensable role in the protein quality control by degrading abnormal organelles and proteins including α-synuclein (αSyn) associated with the pathogenesis of Parkinson’s disease (PD). However, the activation of this pathway is mainly by targeting lysosomal enzymic activity. Here, we focused on the autophagosome-lysosome fusion process around the microtubule-organizing center (MTOC) regulated by lysosomal positioning. Through high-throughput chemical screening, we identified 6 out of 1200 clinically approved drugs enabling the lysosomes to accumulate around the MTOC with autophagy flux enhancement. We further demonstrated that these compounds induce the lysosomal clustering through a JIP4-TRPML1-dependent mechanism. Among them, the lysosomal-clustering compound albendazole promoted the autophagy-dependent degradation of Triton-X-insoluble, proteasome inhibitor-induced aggregates. In a cellular PD model, albendazole boosted insoluble αSyn degradation. Our results revealed that lysosomal clustering can facilitate the breakdown of protein aggregates, suggesting that lysosome-clustering compounds may offer a promising therapeutic strategy against neurodegenerative diseases characterized by the presence of aggregate-prone proteins.
