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dc.contributor.authorHanss, Zoe
dc.contributor.authorLarsen, Simone B
dc.contributor.authorAntony, Paul
dc.contributor.authorMencke, Pauline
dc.contributor.authorMassart, Francois
dc.contributor.authorJarazo, Javier
dc.contributor.authorSchwamborn, Jens C
dc.contributor.authorBarbuti, Peter A
dc.contributor.authorMellick, George D
dc.contributor.authorKruger, Rejko
dc.date.accessioned2021-11-17T04:57:25Z
dc.date.available2021-11-17T04:57:25Z
dc.date.issued2020
dc.identifier.issn0885-3185en_US
dc.identifier.doi10.1002/mds.28365en_US
dc.identifier.urihttp://hdl.handle.net/10072/410175
dc.description.abstractBackground: 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. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.publisherWileyen_US
dc.relation.ispartofpagefrom704en_US
dc.relation.ispartofpageto715en_US
dc.relation.ispartofissue3en_US
dc.relation.ispartofjournalMovement Disordersen_US
dc.relation.ispartofvolume36en_US
dc.subject.fieldofresearchClinical sciencesen_US
dc.subject.fieldofresearchSports science and exerciseen_US
dc.subject.fieldofresearchNeurosciencesen_US
dc.subject.fieldofresearchcode3202en_US
dc.subject.fieldofresearchcode4207en_US
dc.subject.fieldofresearchcode3209en_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsLife Sciences & Biomedicineen_US
dc.subject.keywordsClinical Neurologyen_US
dc.subject.keywordsVPS35en_US
dc.subject.keywordsNeurologyen_US
dc.titleMitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neuronsen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationHanss, Z; Larsen, SB; Antony, P; Mencke, P; Massart, F; Jarazo, J; Schwamborn, JC; Barbuti, PA; Mellick, GD; Kruger, R, Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons, Movement Disorders, 2020, 36 (3), pp. 704-715en_US
dcterms.dateAccepted2020-10-05
dcterms.licensehttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.date.updated2021-10-31T23:17:28Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© The Author(s) 2021. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permitsuse and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifcations or adapta-tions are made.en_US
gro.hasfulltextFull Text
gro.griffith.authorMellick, George


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