Rusilowicz-Jones, Emma, Barone, Francesco 
ORCID: 0000-0003-4382-9313, Lopes, Fernanda Martins, Stephen, Elizabeth, Mortiboys, Heather ORCID: 0000-0001-6439-0579, Urbé, Sylvie and Clague, Michael ORCID: 0000-0003-3355-9479
(2021)
Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy.
2021.04.28.441730-.
Abstract
The deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1/Parkin pathway leading to mitophagy. These include Parkinson’s disease and pulmonary fibrosis. We provide a detailed cell biological characterisation of a benzenesulphonamide 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 following mitochondrial depolarisation. This includes enhancement of TOM20 and SYNJ2BP ubiquitylation and phosphoubiquitin accumulation, alongside increased mitophagy. In dopaminergic neurons, generated from Parkinson’s disease patients carrying loss of function Parkin mutations, compound 39 could significantly restore mitophagy to a level approaching control values. USP30 is located on both mitochondria and peroxisomes and has also been linked to the PINK1 independent pexophagy pathway. Using a fluorescence reporter of pexophagy expressed in U20S cells, we observe increased pexophagy upon application of compound 39 that recapitulates the previously described effect for USP30 depletion. This provides the first pharmacological intervention with a synthetic molecule to enhance peroxisome turnover.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Neurodegenerative, Brain Disorders, Neurosciences, Parkinson's Disease, 5.1 Pharmaceuticals, 5 Development of treatments and therapeutic interventions, Neurological, Generic health relevance |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 03 May 2022 11:15 |
| Last Modified: | 14 Mar 2024 21:26 |
| DOI: | 10.1101/2021.04.28.441730 |
| Open Access URL: | https://www.life-science-alliance.org/content/5/2/... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3154209 |
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