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

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

doi:10.1016/j.isci.2020.101048

Hideyuki Okano, Hidehisa Iwata + Show 7 more

Open Access

https://doi.org/10.1016/j.isci.2020.101048

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Journal: iScience	Publication Date: Apr 11, 2020
Citations: 21	License type: cc-by

Affiliation: Keio University, Takeda (Japan), Juntendo University

Abstract

SummaryEarly-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.

Highlights

Homozygous or compound heterozygous mutations of genes encoding PTEN-inducible kinase 1 (PINK1) and Parkin lead to the selective degeneration of midbrain dopaminergic neurons and cause autosomal recessive early-onset Parkinson’s disease (PD) (Kitada et al, 1998; Valente et al, 2004)
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

Summary

Introduction

Homozygous or compound heterozygous mutations of genes encoding PINK1 and Parkin lead to the selective degeneration of midbrain dopaminergic neurons and cause autosomal recessive early-onset Parkinson’s disease (PD) (Kitada et al, 1998; Valente et al, 2004). Latent Parkin, in the cytosol, is activated and relocalized to the outer mitochondrial membrane, ubiquitinating mitochondrial proteins such as Mitofusin and Miro (Liu et al, 2012; Tanaka et al, 2010; Wang et al, 2011). The ubiquitination and subsequent degradation of Mitofusin and Miro promotes mitochondrial fragmentation and suppresses mitochondrial motility, respectively, and facilitates the autophagic removal of damaged mitochondria (Deng et al, 2008; Liu et al, 2012; Wang et al, 2011; Yang et al, 2008; Ziviani et al, 2010)

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