A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling
Year: 2020
Type: article
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 Ca 2+ 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.
Source: iScience
Institutions: Juntendo University, Takeda (Japan), Keio University
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
Awards: Functional analysis of novel molecules involved in PINK1-Parkin-mediated mitophagy, Autophagy Regulation Mechanism by Parkinson's Disease Causal Gene Product VPS13C, Drug screening to improve mitochondrial functions, Exploration of Parkinson disease-specific pathological background, Analysis of lipid composition in hereditary Parkinson's Disease and the association with the pathology, Generation of an aged Parkinson's disease brain model and elucidation of its pathophysiology using iPS cells, G7028972502
OpenAlex ID: W3016191967