Gene expression and SNP genotype data from induced Pluripotent Stem cells from Parkinson's Disease patients harbouring G2019S mutations in the LRRK2 gene
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PROVIDER: PRJNA311165 | ENA |
REPOSITORIES: ENA
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Project description:We have generated human induced Pluripotent Stem cells (hiPSc) using Retroviral virus-mediated delivery of reprogramming factors. hiPSc lines have been screened using SNP array to assess chromosomal stability (alongside the fibroblast lines from which they derived), and validation of the pluripotency of the hiPSc lines is provided by Pluritest assessment of transcriptome datasets, prior to differentiation and downstream assays. Gene expression profiling in patient-derived dopamine neurons identifies candidate therapeutic molecules in Parkinsonâs disease. human iPSc lines were derived from human dermal fibroblasts from 3 PD LRRK2 G2019S patients and 3 control donors. SNP and gene expression datasets were generated from patient and control lines. Note that iPS OX1-19 and iPS-NHDF-1, also used in the current study, have been published previously so datasets are not given here [GSE45472 PMID:23951090 ; GSE43904 PMID:24586273]
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Project description:Genetic mutations on leucine-rich repeat kinase 2 (LRRK2) have been associated with an increased risk of Parkinson's disease. The Gly2019Ser (G2019S) mutation on LRRK2 gene is a relatively common cause of familial Parkinson's disease in Caucasian population. In this study, we generated human induced pluripotent stem cell (iPSC) lines from LRRK2 (G2019S) bearing patient fibroblasts by cell reprogramming. We performed global gene expression profiling of LRRK2 (G2019S) heterozygous and homozygous patient iPSC lines, and the corresponding fibroblast lines they originated from. An age-matched wildtype human fibroblast line and H1 human embryonic stem cell (ESC) line were used as controls. Microarray gene expression profiling was done to: (1) Compare global gene expression differences between wildtype fibroblasts and fibroblasts from patients bearing homozygous and heterozygous LRRK2 (G2019S) mutation; (2) Compare global gene expression differences between wildtype iPSC and iPSC generated from LRRK2 (G2019S) homozygous and heterozygous patients; (3) Check that all iPSC generated from wildtype and patients fibroblasts are in fact similar to human pluripotent ESC.
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Project description:Recent advances in generating 3 dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson’s disease-associated LRRK2 G2019S mutation. LRRK2-G2019S midbrain organoids derived from LRRK2 targeted human iPSCs in vitro have LRRK2-associated sporadic Parkinson's disease phenotypes. Midbrain-like 3D organoids expressing LRRK2-G2019S showed dynamic changes in globle gene expression.
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Project description:We have generated human induced Pluripotent Stem cells (hiPSc) using Retroviral virus-mediated delivery of reprogramming factors. hiPSc lines have been screened using SNP array to assess chromosomal stability (alongside the fibroblast lines from which they derived), and validation of the pluripotency of the hiPSc lines is provided by Pluritest assessment of transcriptome datasets, prior to differentiation and downstream assays. Gene expression profiling in patient-derived dopamine neurons identifies candidate therapeutic molecules in Parkinsonâ??s disease. human iPSc lines were derived from human dermal fibroblasts from 3 PD LRRK2 G2019S patients and 3 control donors. SNP and gene expression datasets were generated from patient and control lines. Note that iPS OX1-19 and iPS-NHDF-1, also used in the current study, have been published previously so datasets are not given here [GSE45472 PMID:23951090 ; GSE43904 PMID:24586273]
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Project description:Parkinson’s disease (PD) has a neuro-developmental component with multiple genetic predispositions. The most prevalent mutation, LRRK2-G2019S is linked to familial and sporadic PD. Based on the multiple origins of PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patient genetic background act as susceptibility factors for developing PD. To assess the developmental component of LRRK2-G2019S pathogenesis, we used 19 human iPSC-derived neuroepithelial stem cell lines (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal. Within patients, phenotypes were only partly LRRK2-G2019S dependent, suggesting Parkinson’s disease (PD) has a neuro-developmental component with multiple genetic predispositions. The most prevalent mutation, LRRK2-G2019S is linked to familial and sporadic PD. Based on the multiple origins of PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patient genetic background act as susceptibility factors for developing PD. To assess the developmental component of LRRK2-G2019S pathogenesis, we used 19 human iPSC-derived neuroepithelial stem cell lines (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal. Within patients, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. We identified Serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the abberant phenotypes. Its enzymatic product, D-Serine, rescued altered NESC renewal. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment.
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Project description:G2019S mutaion of LRRK2 is known to increase mRNA translation. We perform ribosome profiling to study defective translation using human dopamine neuron models. Patient-derived human dopamine neurons with G2019S LRRK2 mutation were generated and used. Also a mutation-corrected isogenic pair line was used.
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Project description:Genetic mutations on leucine-rich repeat kinase 2 (LRRK2) have been associated with an increased risk of Parkinson's disease. The Gly2019Ser (G2019S) mutation on LRRK2 gene is a relatively common cause of familial Parkinson's disease in Caucasian population. In this study, we generated H9 hESC harboring LRRK2 (G2019S) mutation by gene knockin. Wildtype and LRRK2 mutant hESC were differentiated into NSC using a chemically defined protocol. LRRK2 mutant NSC were treated with or without the LRRK2 kinase specific inhibitor (LRRK2-IN-1). Global gene expression analysis was performed to assess the overall similarity of gene expression profiles among three NSC groups (wildtype; LRRK2 mutant; LRRK2 mutant with inhibitor treatment).
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Project description:Genetic mutations on leucine-rich repeat kinase 2 (LRRK2) have been associated with an increased risk of Parkinson's disease. The Gly2019Ser (G2019S) mutation on LRRK2 gene is a relatively common cause of familial Parkinson's disease in Caucasian population. In this study, we generated human induced pluripotent stem cell (iPSC) lines from LRRK2 (G2019S) bearing patient fibroblasts by cell reprogramming. We performed global gene expression profiling of LRRK2 (G2019S) heterozygous and homozygous patient iPSC lines, and the corresponding fibroblast lines they originated from. An age-matched wildtype human fibroblast line and H1 human embryonic stem cell (ESC) line were used as controls.
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