title: Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation.
abstract: Parkinson's disease (PD) is characterized by the selective loss of dopamine neurons in the substantia nigra; however, the mechanism of neurodegeneration in PD remains unclear. A subset of familial PD is linked to mutations in PARK2 and PINK1, which lead to dysfunctional mitochondria-related proteins Parkin and PINK1, suggesting that pathways implicated in these monogenic forms could play a more general role in PD. We demonstrate that the identification of disease-related phenotypes in PD-patient-specific induced pluripotent stem cell (iPSC)-derived midbrain dopamine (mDA) neurons depends on the type of differentiation protocol utilized. In a floor-plate-based but not a neural-rosette-based directed differentiation strategy, iPSC-derived mDA neurons recapitulate PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. We propose that these form a pathogenic loop that contributes to disease. Our study illustrates the promise of iPSC technology for examining PD pathogenesis and identifying therapeutic targets.
authors.affiliation: Center for Stem Cell Biology, Sloan-Kettering Institute, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 256, New York, NY 10065, USA.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Chung
authors.affiliation: Center for Stem Cell Biology, Sloan-Kettering Institute, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 256, New York, NY 10065, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kishinevsky
authors.affiliation: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mazzulli
authors.affiliation: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: John
authors.initials: J
authors.lastname: Graziotto
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Mrejeru
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Mosharov
authors.affiliation: Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea.
authors.forename: Lesly
authors.initials: L
authors.lastname: Puspita
authors.affiliation: Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea.
authors.forename: Parvin
authors.initials: P
authors.lastname: Valiulahi
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.affiliation: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.affiliation: Center for Stem Cell Biology, Sloan-Kettering Institute, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 256, New York, NY 10065, USA. Electronic address: studerl@mskcc.org.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
authors.affiliation: Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea. Electronic address: shimj@sch.ac.kr.
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Shim
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D008954:Models, Biological; D009154:Mutation; D009928:Organ Specificity; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics*; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051844:alpha-Synuclein / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004298:Dopamine; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein