Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy.

ABSTRACT: The deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1-PRKN pathway leading to mitophagy. We provide a detailed cell biological characterization of a benzosulphonamide molecule, compound 39, that has previously been reported to inhibit USP30 in an in vitro enzymatic assay. The current compound offers increased selectivity over previously described inhibitors. It enhances mitophagy and generates a signature response for USP30 inhibition after mitochondrial depolarization. This includes enhancement of TOMM20 and SYNJ2BP ubiquitylation and phosphoubiquitin accumulation, alongside increased mitophagy. In dopaminergic neurons, generated from Parkinson disease patients carrying loss of function PRKN mutations, compound 39 coul

SUBMITTER: Rusilowicz-Jones EV 

PROVIDER: S-EPMC8645336 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature