title: Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells.
abstract: We have assessed the impact of α-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of α-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction.
authors.affiliation: Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, Germany.
authors.forename: L M A
authors.initials: LM
authors.lastname: Oliveira
authors.affiliation: Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, Germany.
authors.forename: L J
authors.initials: LJ
authors.lastname: Falomir-Lockhart
authors.affiliation: Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, Germany.
authors.forename: M G
authors.initials: MG
authors.lastname: Botelho
authors.affiliation: Group of Membrane Biophysics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, Germany.
authors.forename: K-H
authors.initials: KH
authors.lastname: Lin
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Waldweg 33, Göttingen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Wales
authors.affiliation: Department of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, Göttingen, Germany.
authors.forename: J C
authors.initials: JC
authors.lastname: Koch
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Waldweg 33, Göttingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Gerhardt
authors.affiliation: Group of Membrane Biophysics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, Germany.|DFG-Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Taschenberger
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Waldweg 33, Göttingen, Germany.|DFG-Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: T F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Department of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, Göttingen, Germany.|DFG-Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: P
authors.identifier: http://orcid.org/0000-0001-9362-7096
authors.initials: P
authors.lastname: Lingor
authors.affiliation: The Parkinson's Institute, 675 Almanor Ave., Sunnyvale, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Schüle
authors.affiliation: Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, Germany.
authors.forename: D J
authors.initials: DJ
authors.lastname: Arndt-Jovin
authors.affiliation: Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, Germany.
authors.forename: T M
authors.initials: TM
authors.lastname: Jovin
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein