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Cell Rep. 2014 Nov 20;9(4):1173-82. doi: 10.1016/j.celrep.2014.10.023. Epub 2014 Nov 6.

iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease.

Author information

1
The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
2
Department of Neurology, Columbia University, New York, NY 10032, USA.
3
Department of Neurology, NYU School of Medicine, New York, NY 10016, USA.
4
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.
5
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
6
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Genzyme Corporation, a Sanofi Company, Framingham, MA 01701, USA.
8
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.
9
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.
10
Axion Biosystems, 1819 Peachtree Road, Suite 350, Atlanta, GA 30309, USA.
11
The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA. Electronic address: ali@nyscf.org.
12
The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA. Electronic address: snoggle@nyscf.org.

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.

PMID:
25456120
PMCID:
PMC4255586
DOI:
10.1016/j.celrep.2014.10.023
[Indexed for MEDLINE]
Free PMC Article

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