Dataset Information

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 ?-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 ?-synuclein and dopamine levels, suggesting a combination therapy for the affected twin.

SUBMITTER: Woodard CM

PROVIDER: S-EPMC4255586 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Woodard Chris M CM Campos Brian A BA Kuo Sheng-Han SH Nirenberg Melissa J MJ Nestor Michael W MW Zimmer Matthew M Mosharov Eugene V EV Sulzer David D Zhou Hongyan H Paull Daniel D Clark Lorraine L Schadt Eric E EE Sardi Sergio Pablo SP Rubin Lee L Eggan Kevin K Brock Mathew M Lipnick Scott S Rao Mahendra M Chang Stephen S Li Aiqun A Noggle Scott A SA

Cell reports 20141106 4

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 ...[more]

PMID: 25456120

Similar Datasets

Project description:Although monozygotic (MZ) twins share the majority of their genetic makeup, they can be phenotypically discordant on several traits and diseases. DNA methylation is an epigenetic mechanism that can be influenced by genetic, environmental and stochastic events and may have an important impact on individual variability. In this study we explored epigenetic differences in peripheral blood samples in three MZ twin studies on major depressive disorder (MDD). Epigenetic data for twin pairs were collected as part of a previous study using 8.1-K-CpG microarrays tagging DNA modification in white blood cells from MZ twins discordant for MDD. Data originated from three geographical regions: UK, Australia and the Netherlands. Ninety-seven MZ pairs (194 individuals) discordant for MDD were included. Different methods to address non independently-and-identically distributed (non-i.i.d.) data were evaluated. Machine-learning methods with feature selection centered on support vector machine and random forest were used to build a classifier to predict cases and controls based on epivariations. The most informative variants were mapped to genes and carried forward for network analysis. A mixture approach using principal component analysis (PCA) and Bayes methods allowed to combine the three studies and to leverage the increased predictive power provided by the larger sample. A machine-learning algorithm with feature reduction classified affected from non-affected twins above chance levels in an independent training-testing design. Network analysis revealed gene networks centered on the PPAR-γ (NR1C3) and C-MYC gene hubs interacting through the AP-1 (c-Jun) transcription factor. PPAR-γ (NR1C3) is a drug target for pioglitazone, which has been shown to reduce depression symptoms in patients with MDD. Using a data-driven approach we were able to overcome challenges of non-i.i.d. data when combining epigenetic studies from MZ twins discordant for MDD. Individually, the studies yielded negative results but when combined classification of the disease state from blood epigenome alone was possible. Network analysis revealed genes and gene networks that support the inflammation hypothesis of MDD.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets