2. Academic Validation
  3. A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling

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.
Kahori Shiba-Fukushima 1,  Tsuyoshi Inoshita 1,  Osamu Sano 2,  Hidehisa Iwata 2,  Kei-Ichi Ishikawa 3,  Hideyuki Okano 4,  Wado Akamatsu 5,  Yuzuru Imai 6,  Nobutaka Hattori 7
Affiliations

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.
PMID: 32335362 DOI: 10.1016/j.isci.2020.101048
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z