A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling

Kahori Shiba-Fukushima; Tsuyoshi Inoshita; Osamu Sano; Hidehisa Iwata; Kei-Ichi Ishikawa; Hideyuki Okano; Wado Akamatsu; Yuzuru Imai; Nobutaka Hattori

doi:10.1016/j.isci.2020.101048

A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling

iScience. 2020 May 22;23(5):101048. doi: 10.1016/j.isci.2020.101048. Epub 2020 Apr 11.

Authors

Kahori Shiba-Fukushima¹, Tsuyoshi Inoshita¹, Osamu Sano², Hidehisa Iwata², Kei-Ichi Ishikawa³, Hideyuki Okano⁴, Wado Akamatsu⁵, Yuzuru Imai⁶, Nobutaka Hattori⁷

Affiliations

¹ Department of Treatment and Research in Multiple Sclerosis and Neuro-intractable Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
² BioMolecular Research Laboratories, Takeda Pharmaceutical Company, Fujisawa, Kanagawa 251-8555, Japan.
³ Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Neurology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
⁴ Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
⁵ Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
⁶ 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. Electronic address: yzimai@juntendo.ac.jp.
⁷ Department of Treatment and Research in Multiple Sclerosis and Neuro-intractable Disease, Juntendo University Graduate School of Medicine, 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. Electronic address: nhattori@juntendo.ac.jp.

Abstract

Early-onset Parkinson's disease-associated PINK1-Parkin signaling maintains mitochondrial health. Therapeutic approaches for enhancing PINK1-Parkin signaling present a potential strategy for treating various diseases caused by mitochondrial dysfunction. We report two chemical enhancers of PINK1-Parkin signaling, identified using a robust cell-based high-throughput screening system. These small molecules, T0466 and T0467, activate Parkin mitochondrial translocation in dopaminergic neurons and myoblasts at low doses that do not induce mitochondrial accumulation of PINK1. Moreover, both compounds reduce unfolded mitochondrial protein levels, presumably through enhanced PINK1-Parkin signaling. These molecules also mitigate the locomotion defect, reduced ATP production, and disturbed mitochondrial Ca²⁺ response in the muscles along with the mitochondrial aggregation in dopaminergic neurons through reduced PINK1 activity in Drosophila. Our results suggested that T0466 and T0467 may hold promise as therapeutic reagents in Parkinson's disease and related disorders.

Keywords: Biological Sciences; Cell Biology; Neuroscience.