Universität zu Köln

Polachova, Edita, Bach, Kathrin, Heuten, Elena, Stanchev, Stancho, Ticha, Anezka, Lampe, Philipp, Majer, Pavel, Langer, Thomas, Lemberg, Marius K. and Strisovsky, Kvido (2023). Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy. J. Med. Chem., 66 (1). S. 251 - 266. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4804

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Abstract

The mitochondrial rhomboid protease PARL regulates mitophagy by balancing intramembrane proteolysis of PINK1 and PGAM5. It has been implicated in the pathogenesis of Parkinson's disease, but its investigation as a possible therapeutic target is challenging in this context because genetic deficiency of PARL may result in compensatory mechanisms. To address this problem, we undertook a hitherto unavailable chemical biology strategy. We developed potent PARL-targeting ketoamide inhibitors and investigated the effects of acute PARL suppression on the processing status of PINK1 intermediates and on Parkin activation. This approach revealed that PARL inhibition leads to a robust activation of the PINK1/Parkin pathway without major secondary effects on mitochondrial properties, which demonstrates that the pharmacological blockage of PARL to boost PINK1/Parkin-dependent mitophagy is a feasible approach to examine novel therapeutic strategies for Parkinson's disease. More generally, this study showcases the power of ketoamide inhibitors for cell biological studies of rhomboid proteases.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Polachova, Edita UNSPECIFIED UNSPECIFIED UNSPECIFIED Bach, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Heuten, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Stanchev, Stancho UNSPECIFIED UNSPECIFIED UNSPECIFIED Ticha, Anezka UNSPECIFIED UNSPECIFIED UNSPECIFIED Lampe, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Majer, Pavel UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Lemberg, Marius K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Strisovsky, Kvido UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-679530
DOI:	10.1021/acs.jmedchem.2c01092
Journal or Publication Title:	J. Med. Chem.
Volume:	66
Number:	1
Page Range:	S. 251 - 266
Date:	2023
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	1520-4804
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LIPID-BILAYER NANODISCS; MEMBRANE-PROTEINS; PINK1; PARKIN; CLEAVAGE; PROTEOLYSIS; MATURATION; MECHANISM; IMPORT Multiple languages Chemistry, Medicinal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67953