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
Affiliations
Kahori Shiba-Fukushima
Department of Treatment and Research in Multiple Sclerosis and Neuro-intractable Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
Tsuyoshi Inoshita
Department of Treatment and Research in Multiple Sclerosis and Neuro-intractable Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
Osamu Sano
BioMolecular Research Laboratories, Takeda Pharmaceutical Company, Fujisawa, Kanagawa 251-8555, Japan
Hidehisa Iwata
BioMolecular Research Laboratories, Takeda Pharmaceutical Company, Fujisawa, Kanagawa 251-8555, Japan
Kei-ichi Ishikawa
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
Hideyuki Okano
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
Wado Akamatsu
Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
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
Nobutaka Hattori
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; Corresponding author
Summary: 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.
