title: iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease.
abstract: Parkinson's disease (PD) has been attributed to a combination of genetic and nongenetic factors. We studied a set of monozygotic twins harboring the heterozygous glucocerebrosidase mutation (GBA N370S) but clinically discordant for PD. We applied induced pluripotent stem cell (iPSC) technology for PD disease modeling using the twins' fibroblasts to evaluate and dissect the genetic and nongenetic contributions. Utilizing fluorescence-activated cell sorting, we obtained a homogenous population of "footprint-free" iPSC-derived midbrain dopaminergic (mDA) neurons. The mDA neurons from both twins had ∼50% GBA enzymatic activity, ∼3-fold elevated α-synuclein protein levels, and a reduced capacity to synthesize and release dopamine. Interestingly, the affected twin's neurons showed an even lower dopamine level, increased monoamine oxidase B (MAO-B) expression, and impaired intrinsic network activity. Overexpression of wild-type GBA and treatment with MAO-B inhibitors normalized α-synuclein and dopamine levels, suggesting a combination therapy for the affected twin.
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Woodard
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Campos
authors.affiliation: Department of Neurology, Columbia University, New York, NY 10032, USA.
authors.forename: Sheng-Han
authors.initials: SH
authors.lastname: Kuo
authors.affiliation: Department of Neurology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Nirenberg
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Nestor
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zimmer
authors.affiliation: Department of Neurology, Columbia University, New York, NY 10032, USA.
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Mosharov
authors.affiliation: Department of Neurology, Columbia University, New York, NY 10032, USA; Departments of Psychiatry, Pharmacology, Columbia University, New York, NY 10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Paull
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Clark
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Genzyme Corporation, a Sanofi Company, Framingham, MA 01701, USA.
authors.forename: Sergio Pablo
authors.initials: SP
authors.lastname: Sardi
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Rubin
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Stanley Center for Psychiatric Research, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
authors.affiliation: Axion Biosystems, 1819 Peachtree Road, Suite 350, Atlanta, GA 30309, USA.
authors.forename: Mathew
authors.initials: M
authors.lastname: Brock
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Lipnick
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Rao
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chang
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA. Electronic address: ali@nyscf.org.
authors.forename: Aiqun
authors.initials: A
authors.lastname: Li
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA. Electronic address: snoggle@nyscf.org.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Noggle
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D005434:Flow Cytometry; D005962:Glucosylceramidase / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000201:enzymology / Q000473:pathology*; D010641:Phenotype; D017423:Sequence Analysis, RNA; D014430:Twins, Monozygotic; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D015415:Biomarkers; D008996:Monoamine Oxidase Inhibitors; D051844:alpha-Synuclein; D008995:Monoamine Oxidase; D005962:Glucosylceramidase; D004298:Dopamine