Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice
BMC Seminar Thursday May 11 at 12:00 in Læknagarður, room 201
Name: Dr. Francois Singh, Assistant Professor, University of Iceland
Title: Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice
Abstract: Parkinson’s disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its etiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation – key features of the autophagy of mitochondria, known as mitophagy. Here, we investigated the role of LRRK2, a protein kinase frequently mutated in PD, in this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson’s disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.
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Short bio: Dr. Francois Singh obtained his PhD in Cellular and molecular aspects of Biology in 2016 from the University of Strasbourg (France). His PhD project was realised in co-direction between the Clinical Pharmacology and Toxicology lab of Professor Stephan Krähenbühl at the University of Basel (Switzerland) and the EA3072: Mitochondria, Oxidative Stress and Muscular Protection Lab of Professor Bernard Geny at the University of Strasbourg (France). He investigated the role of mitochondrial adaptations in statin-induced myotoxicity, focusing on the opposite effect of statins in glycolytic and in oxidative muscles. During that time, he also taught medical students at the University hospital of Strasbourg Physiology, as well as Toxicology students at the Department of Pharmaceutical Sciences in Basel.
In 2017, he joined the lab of Professor Ian Ganley as a postdoctoral research assistant at the MRC-Protein Phosphorylation and ubiquitylation unit, University of Dundee, United Kingdom, in collaboration with GlaxoSmithKline. His project investigated the physiological role of pathogenic mutations involved in Parkinson’s disease on mitophagy and general autophagy in vivo. His work provided the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy and demonstrated that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.
In 2023, Francois became Assistant Professor at the department of Physiology, School of Health Sciences, University of Iceland.