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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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Woodard CM,Campos BA,Kuo SH,Nirenberg MJ,Nestor MW,Zimmer M,Mosharov EV,Sulzer D,Zhou H,Paull D,Clark L,Schadt EE,Sardi SP,Rubin L,Eggan K,Brock M,Lipnick S,Rao M,Chang S,Li A,Noggle SA

doi

10.1016/j.celrep.2014.10.023

subject

Has Abstract

pub_date

2014-11-20 00:00:00

pages

1173-82

issue

4

issn

2211-1247

pii

S2211-1247(14)00877-8

journal_volume

9

pub_type

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