Developmental Dieldrin Exposure Alters DNA Methylation at Genes Related to Dopaminergic Neuron Development and Parkinson’s Disease in Mouse Midbrain
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ABSTRACT:
PROVIDER: PRJNA555989 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9729140_1.fastq.gz | Fastqsanger.gz | |||
| SRR9729140_2.fastq.gz | Fastqsanger.gz | |||
| SRR9729150_1.fastq.gz | Fastqsanger.gz | |||
| SRR9729150_2.fastq.gz | Fastqsanger.gz | |||
| SRR9729160_1.fastq.gz | Fastqsanger.gz |
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Project description:Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson’s disease (PD). Despite previous work showing a link between developmental dieldrin exposure and increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, the mechanism mediating this effect has not been identified. Here, we tested the hypothesis that developmental exposure to dieldrin increases neuronal susceptibility via genome-wide changes in DNA methylation. Starting at 8 weeks of age and prior to mating, female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin by feeding (every 3 days) throughout breeding, gestation, and lactation. At 12 weeks of age, pups were sacrificed and midbrains were dissected. DNA was isolated and dieldrin-related changes in DNA methylation were assessed via reduced representation bisulfite sequencing (RRBS). We identified significant, sex-specific differentially methylated CpGs (DMCs) and regions (DMRs) by developmental dieldrin exposure (FDR<0.05), including DMCs at the Nr4a2 and Lmx1b genes, which are involved in dopaminergic neuron development and maintenance. Developmental dieldrin exposure had distinct effects on the male and female epigenome. Furthermore, a separate set of changes in DNA methylation was identified after adult exposure to dieldrin, suggesting that adult and developmental dieldrin toxicity may not act through a shared epigenetic mechanism. Together, our data suggest that developmental dieldrin exposure establishes sex-specific poised epigenetic states early in life. These poised epigenomes may mediate sensitivity to additional environmental stimuli and contribute to the development of late-life neurodegenerative disease, including PD.
2019-07-23 | GSE134636 | GEO
Project description:In order to get a better molecular understanding of human midbrain development, this study defines cell types of the ventral midbrain in both human and mouse as well as stem cell-derived dopaminergic neuron preparations, and reveals the temporal dynamics of key lineages across development and the adult.
2016-10-06 | GSE76381 | GEO
Project description:Epidemiological studies show that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson’s disease (PD). Animal studies support a link between developmental dieldrin exposure and increased neuronal susceptibility in the α-synuclein preformed fibril (α-syn PFF) and MPTP models in adult male C57BL/6 mice. In a previous study, we showed that developmental dieldrin exposure was associated with sex-specific changes in DNA modifications within genes related to dopaminergic neuron development and maintenance at 12 weeks of age. Here, we used capture hybridization-sequencing with custom baits to interrogate DNA modifications across the entire genetic loci of the previously identified genes at multiple time points – birth, 6 weeks, 12 weeks, and 36 weeks old. We identified largely sex-specific dieldrin-induced changes in DNA modifications at each time point that annotated to pathways important for neurodevelopment, potentially related to critical steps in early neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, synaptic plasticity, and glial-neuron interactions. Despite large numbers of age-specific DNA modifications, longitudinal analysis identified a small number of DMCs with dieldrin-induced deflection of epigenetic aging. The sex-specificity of these results adds to evidence that sex-specific responses to PD-related exposures may underly sex-specific differences in disease. Overall, these data support the idea that developmental dieldrin exposure leads to changes in epigenetic patterns that persist after the exposure period has ended and disrupt critical neurodevelopmental pathways and that developmental exposures can impact risk of late life diseases, including PD.
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Project description:Advances in stem cell technologies open up new avenues for modelling development and diseases. The success of these pursuits however rely on the use of cells most relevant to those targeted by the disease of interest, for example, midbrain dopaminergic neurons for Parkinson’s disease. In the present study, we report the generation of a human induced pluripotent stem cell (iPSC) line capable of purifying and tracing nascent midbrain dopaminergic progenitors and their differentiated progeny via the expression of a Blue Fluorescent Protein (BFP). This was achieved by CRISPR/Cas9 assisted knock-in of BFP and Cre into the safe harbour locus AAVS1 and an early midbrain dopaminergic lineage marker gene LMX1A, respectively. Immunocytochemical analysis and single cell RNA sequencing of iPSC-derived neural cultures confirms developmental recapitulation of the human fetal midbrain and high quality midbrain cells. By modelling Parkinson’s disease-related drug toxicity using 1-Methyl-4-phenylpyridinium (MPP+), we showed preferential reduction of BFP+ cells, a finding demonstrated independently by cell death assays and single cell transcriptomic analysis of MPP+ treated neural cultures. Together, these results highlight the importance of disease relevant cell type in stem cell modelling.
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Project description:Advances in stem cell technologies open up new avenues for modelling development and diseases. The success of these pursuits however rely on the use of cells most relevant to those targeted by the disease of interest, for example, midbrain dopaminergic neurons for Parkinson’s disease. In the present study, we report the generation of a human induced pluripotent stem cell (iPSC) line capable of purifying and tracing nascent midbrain dopaminergic progenitors and their differentiated progeny via the expression of a Blue Fluorescent Protein (BFP). This was achieved by CRISPR/Cas9 assisted knock-in of BFP and Cre into the safe harbour locus AAVS1 and an early midbrain dopaminergic lineage marker gene LMX1A, respectively. Immunocytochemical analysis and single cell RNA sequencing of iPSC-derived neural cultures confirms developmental recapitulation of the human fetal midbrain and high quality midbrain cells. By modelling Parkinson’s disease-related drug toxicity using 1-Methyl-4-phenylpyridinium (MPP+), we showed preferential reduction of BFP+ cells, a finding demonstrated independently by cell death assays and single cell transcriptomic analysis of MPP+ treated neural cultures. Together, these results highlight the importance of disease relevant cell type in stem cell modelling.
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Project description:Mutations in the SNCA gene cause autosomal dominant Parkinson’s disease (PD), with progressive loss of dopaminergic neurons in the substantia nigra, and accumulation of aggregates of α-synuclein. However, the sequence of molecular events that proceed from the SNCA mutation during development, to its end stage pathology is unknown. Utilising human induced pluripotent stem cells (hiPSCs) with SNCA mutations, we resolved the temporal sequence of pathophysiological events that occur during neuronal differentiation in order to discover the early, and likely causative, events in synucleinopathies. We adapted a small molecule-based protocol that generates highly enriched midbrain dopaminergic (mDA) neurons (>80%). We characterised their molecular identity using single-cell RNA sequencing and their functional identity through the synthesis and secretion of dopamine, the ability to generate action potentials, and form functional synapses and networks. RNA velocity analyses confirmed the developmental transcriptomic trajectory of midbrain neural precursors into different mDA neuronal clusters. To characterise the synucleinopathy, we adopted super-resolution methods to determine the number, size, and structure of aggregates in SNCA-mutant mDA neurons. By day 27 of differentiation, prior to maturation to mDA neurons of molecular and functional identity, we demonstrate the formation of small aggregates; specifically, β-sheet rich oligomeric aggregates, in SNCA-mutant midbrain immature neurons. The aggregation progresses over time to accumulate phosphorylated and fibrillar aggregates. When the midbrain neurons were functional, we observed impaired intracellular calcium signalling, evidenced with an increased basal calcium level and impairments in both cytosolic and mitochondrial calcium rearrangements. Once midbrain identity fully developed, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling as well as an upregulation of mitophagy and autophagy. In addition, SNCA-mutant neurons displayed pathophysiological excitability, revealed as a depolarised resting membrane potential, an increased input resistance, and impaired firing properties. Ultimately these multiple cellular stresses lead to an increase in cell death by day 62 post-differentiation. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD, and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.
2023-03-11 | PXD035500 | Pride
Project description:Parkinson’s disease, one of the most common aging-associated neurodegenerative disorders, is characterised by nigrostriatal pathway dysfunction, caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the dopamine depletion in the striatum. State of the art, human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation of the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics necessary for the development of PD. Therefore, it is conceivable that research conducted using these models overlooked numerous processes that contribute to disease’s phenotypes. Here we present a method for the generation of a midbrain-striatum assembloid model with inducible aging. Aging is induced by expression of progerin. We show that these assembloids are capable of developing characteristics of the nigrostriatal connectivity, with dopamine release from the midbrain to striatum and synapses formation between midbrain and striatal neurons. Moreover, progerin-overexpressing assembloids acquire aging phenotypes that lead to early phenotypes of Parkinson’s disease. This new model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of PD.
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Project description:Growing evidence indicates that Type 2 diabetes (T2D) is associated with an increased risk of developing PD Parkinson’s disease (PD) through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism, and survival. To better understand the importance of insulin signalling in the human midbrain, which is the most affected brain region in PD, we expose IPSC-derived human midbrain organoids from healthy individuals and GBA-N370S mutation-carrying PD patients to either high insulin concentrations, promoting insulin resistance, or to more physiological insulin concentrations restoring normal insulin signalling function. We are able to show that insulin resistance compromises dopaminergic neuron and dopamine levels in the midbrain organoids of healthy donors. Moreover, insulin-resistant organoids display diminished neuronal activity and reduced metabolic efficiency. Furthermore, our findings demonstrate FOXO1 role in GBA-PD phenotype severity and show the potential beneficial effects of the anti-diabetic drug Pioglitazone in GBA-PD treatment. Overall, our results highlight insulin resistance as a significant target in PD prevention and disease-modifying therapy.
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