Reference : Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons
Scientific journals : Article
Life sciences : Genetics & genetic processes
Systems Biomedicine
http://hdl.handle.net/10993/46008
Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons
English
Hanss, Zoé mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >]
Larsen, Simone mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Antony, Paul mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >]
Mencke, Pauline mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >]
Massart, François mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >]
Jarazo, Javier mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Schwamborn, Jens Christian mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology >]
Barbuti, Peter mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Mellick, George mailto []
Krüger, Rejko mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience >]
3-Nov-2020
Movement Disorders
John Wiley & Sons
Yes (verified by ORBilu)
International
0885-3185
1531-8257
Hoboken
NY
[en] VPS35 ; induced pluripotent stem cells ; mitochondrial impairment ; Parkinson's disease ; alpha-synuclein
[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
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
Fonds National de la Recherche - FnR ; European Commission - EC ; Fondation du Pelican
Researchers
http://hdl.handle.net/10993/46008
10.1002/mds.28365
https://onlinelibrary.wiley.com/doi/10.1002/mds.28365
H2020 ; 692320 - CENTRE-PD - TWINNING for a Comprehensive Clinical Centre for the Diagnosis and Treatment of Parkinson's Disease
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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