Reference : Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons

	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Genetics & genetic processes
	Focus Areas :	Systems Biomedicine
	To cite this reference:	http://hdl.handle.net/10993/46008

Title :	Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons
Language :	English
Author, co-author :	Hanss, Zoé [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >]
	Larsen, Simone [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	Antony, Paul [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >]
	Mencke, Pauline [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >]
	Massart, François [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >]
	Jarazo, Javier [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	Schwamborn, Jens Christian [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology >]
	Barbuti, Peter [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	Mellick, George []
	Krüger, Rejko [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >]
Publication date :	3-Nov-2020
Journal title :	Movement Disorders
Publisher :	John Wiley & Sons
Peer reviewed :	Yes (verified by ORBilu)
Audience :	International
ISSN :	0885-3185
e-ISSN :	1531-8257
City :	Hoboken
Country :	NY
Keywords :	[en] VPS35 ; induced pluripotent stem cells ; mitochondrial impairment ; Parkinson's disease ; alpha-synuclein
Abstract :	[en] Background: VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation of mitochondrial proteins via mitochondria-derived vesicles. The p.D620N mutation of VPS35 causes an autosomal-dominant form of Parkinson’s disease (PD), clinically representing typical PD. Objective: Most of the studies on p.D620N VPS35 were performed on human tumor cell lines, rodent models overexpressing mutant VPS35, or in patient-derived fibroblasts. Here, based on identified target proteins, we investigated the implication of mutant VPS35 in autophagy, lysosomal degradation, and mitochondrial function in induced pluripotent stem cell-derived neurons from a patient harboring the p.D620N mutation. Methods: We reprogrammed fibroblasts from a PD patient carrying the p.D620N mutation in the VPS35 gene and from two healthy donors in induced pluripotent stem cells. These were subsequently differentiated into neuronal precursor cells to finally generate midbrain dopaminergic neurons. Results: We observed a decreased autophagic flux and lysosomal mass associated with an accumulation of α-synuclein in patient-derived neurons compared to controls. Moreover, patient-derived neurons presented a mitochondrial dysfunction with decreased membrane potential, impaired mitochondrial respiration, and increased production of reactive oxygen species associated with a defect in mitochondrial quality control via mitophagy. Conclusion: We describe for the first time the impact of the p.D620N VPS35 mutation on autophago-lysosome pathway and mitochondrial function in stem cell-derived neurons from an affected p.D620N carrier and define neuronal phenotypes for future pharmacological interventions
Research centres :	Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) ; Griffith Institute for Drug Discovery
Funders :	Fonds National de la Recherche - FnR ; European Commission - EC ; Fondation du Pelican
Target :	Researchers
Permalink :	http://hdl.handle.net/10993/46008
DOI :	10.1002/mds.28365
Other URL :	https://onlinelibrary.wiley.com/doi/10.1002/mds.28365
Framework Programme / European Project :	H2020 ; 692320 - CENTRE-PD - TWINNING for a Comprehensive Clinical Centre for the Diagnosis and Treatment of Parkinson's Disease
FnR project :	FnR ; FNR6682797 > Rejko Krüger > Endophenotypes in Neurodegeneration > Comprehensive assessment of endophenotypes in neurodegenerative diseases - translating impaired molecular signalling pathways into novel therapeutic strategies for Parkinson’s disease > 01/06/2014 > 31/05/2019 > 2013

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