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Gene expression of hiPSC-derived DA Neurons harboring SNCA A53T mutation or genome Corrected and hESC-derived WT DA Neurons and SNCA A53T mutation introduced Corrected

ABSTRACT: A53T mutant human DA neurons or their isogenic control counterparts were differentiated to DA-Neurons for 35 days. Gene expression profile was analysed to assess the effect of the genetype on gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131597 | GEO | 2019/06/25

REPOSITORIES: GEO

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Gene expression of hiPSC-derived DA Neurons harboring SNCA A53T mutation or genome Corrected and hESC-derived WT DA Neurons and SNCA A53T mutation introduced Corrected

Project description:Gene expression of hiPSC-derived DA Neurons harboring SNCA A53T mutation or genome Corrected and hESC-derived WT DA Neurons and SNCA A53T mutation introduced Corrected

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Gene expression of A53T and corrected IPSC driven to DA neurons and exposed to paraquat and maneb

Project description:Parkinson disease (PD) is characterized by extensive loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). A strong association has been reported between PD and exposure to mitochondrial toxins such as the environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived, stem cell model of PD that allows comparison of -synuclein ( -syn) mutant cells and isogeneic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations specific to A53T -syn mutant A9-DA neurons (hNs). We report a novel molecular pathway whereby basal as well as toxin-induced oxidative and nitrosative stress inhibits the MEF2C-PGC1 transcription network in A53T hNs compared to corrected controls, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small molecule high-throughput screening, we identify the MEF2C-PGC1 pathway as a new drug target for therapeutic benefit in PD. In the current study, isogenic hiPSCs differing exclusively at a single amino acid (A53T) were exposed to either 2.8uM paraquat in combination with 1uM maneb for 24h or PBS vehicle control. Gene expression profile was analysed to assess the effect of both the genotype and exposure regiment on gene expression.

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Transcriptional Profiling of Class IV da Neurons

Project description:Elucidating the molecular mechanisms controlling dendrite development is key to understanding the pivotal role these structures play in influencing synaptic integration and neural function. Despite significant advances in this field, genetic pleiotropy remains a significant impediment to investigating such complex developmental processes. To circumvent this problem, we have applied class specific neuron transcriptional expression profiling coupled to an in vivo RNAi functional validation screen in order to dissect the molecular bases of Drosophila class IV dendritic arborization (da) neuron dendritogenesis. Microarray analyses reveal transcriptional regulation as one highly enriched biological and functional category with 420 transcription factors significantly expressed in class IV neurons. Among these, we identify roles for 268 genes in mediating a broad spectrum of functions including dendritic field coverage, branching, routing, and tiling. Collectively, our analyses provide a more comprehensive framework of the role complex transcriptional networks play in directing distinct aspects of class specific dendrite morphogenesis. Gene expression profiling of class IV da neurons performed at the third instar larval stage of development from two independent cell isolations from 40-50 age-matched third instar larvae expressing mCD8::GFP under the control of the GAL4ppk.1.9 driver

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Expression profiling of isolated dendritic arborization (da) neurons of Drosophila

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Project description:Induced pluripotent stem cells (iPSCs) are a promising source for cell-based therapy to treat Parkinson's disease (PD), in which midbrain dopaminegic (DA) neurons progressively degenerate. However, long-term analysis of human iPSC-derived DA neurons in primate PD models has never been performed. Here we show that DA progenitor cells derived from iPSCs of both healthy individuals and PD patients survived well in the brains of PD model primates and improved animal behavior. Magnetic resonance and positron emission tomography were useful to monitor the survival and function of the DA neurons. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature DA neurons extended dense neurites into the host striatum. In addition, we never observed tumor formation for two years. Thus, this preclinical study using primate models indicates that human iPSC-derived DA progenitors are clinically applicable to treat PD patients.

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Detailed analysis of the genetic and epigenetic signature of iPS cell-derived mesodiencephalic dopaminergic neurons

Project description:Induced pluripotent stem cells (iPSCs) harbor great promise for in vitro generation of disease-relevant cell types, such as mesodiencephalic dopaminergic (mdDA) neurons involved in Parkinson’s disease. Although iPSC-derived midbrain DA neurons have been generated, detailed genetic and epigenetic characterization of such neurons is still lacking. The goal of this study is to examine the authenticity of iPSC-derived DA neurons obtained by established protocols. We FACS-purified mdDA (Pitx3gfp/+) neurons derived from mouse iPSCs and primary mdDA (Pitx3gfp/+) neurons to analyze and compare their genetic and epigenetic features. Although iPSC-derived DA neurons largely adopt characteristics of their in-vivo counterparts, relevant deviations in global gene expression and DNA methylation were found. Hypermethylated genes, mainly involved in neurodevelopment and basic neuronal functions, consequently showed reduced expression levels. Such abnormalities should be addressed as they might affect unambiguous long-term functionality and hamper the potential of iPSC-derived DA neurons for in-vitro disease modeling or cell-based therapy. RRBS methylation maps were generated for iPSCs cells, dopaminergic neurons derived from iPSCs and primary mesodiencephalic dopaminergic neurons

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