Gene expression of A53T and corrected IPSC driven to DA neurons and exposed to paraquat and maneb
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE46798 | GEO | 2013/12/05
SECONDARY ACCESSION(S): PRJNA202312
REPOSITORIES: GEO
Similar Datasets
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.
2013-12-05 | E-GEOD-46798 | biostudies-arrayexpress
Project description:Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that is characterized by the selective loss of midbrain dopamine (DA)-producing neurons and the formation of α-synuclein (α-syn)-containing inclusions named Lewy bodies (LBs). Here, we report that the loss of glucocerebrosidase (GCase), coupled with α-syn overexpression, result in substantial accumulation of detergent-resistant α-syn aggregates and Lewy body-like inclusions (LBLIs) in human midbrain-like organoids (hMLOs). These LBLIs exhibit a highly similar structure to PD-associated LBs, by displaying a spherically symmetric morphology with an eosinophilic core, and containing α-syn and ubiquitin. Importantly, hMLOs generated from PD patient-derived inducible pluripotent stem cells (iPSCs) harboring SNCA triplication also exhibit subsequent degeneration of DA neurons and LBLI formation upon chronic GCase inhibitor treatment. Taken together, our hMLOs harbouring two major PD risk factors (GCase deficiency and overproduced α-syn) successfully recapitulate major pathophysiological signatures of the disease, and highlight the broad utility of brain organoid technology in modeling human neurodegenerative diseases.
2021-08-13 | E-MTAB-7302 | biostudies-arrayexpress
Project description:Parkinsonâs disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse. Parkinsonâs disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse. Tissue was dissected from the brain of 6 months old (2 WT / 2 TgA / 2 TgB striata, 2 WT / 2 TgA / 2 TgB brainstems/midbrains, 2 WT / 2 TgA / 2 TgB cerebella) and of 18+ months old mice (4 WT / 2 TgA / 2 TgB striata, 6 WT / 4 TgA / 3 TgB brainstems/midbrains, 6 WT / 5 TgA / 4 TgB cerebella). Tissues from individual, particularly old mice up to 28 months age were included here to strengthen the definition of progression markers reflecting old age.
2010-05-27 | E-GEOD-20547 | biostudies-arrayexpress
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
| PRJNA544108 | ENA
Project description:Parkinson’s disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse. Parkinson’s disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse.
2010-05-01 | GSE20547 | GEO
Project description:The lack of appropriate protein biomarkers makes the early detection of Parkinson’s disease (PD) challenging, and it thwarts efforts to develop drug therapies for this incurable disease. Thus, new approaches are needed for biomarker discovery and for better understanding the molecular basis of PD progression. Here, we utilize proteome-wide measurements of protein folding stability to characterize the progression of PD in a mouse model of the disease in which the human α-synuclein protein with an A53T mutation was overexpressed. Using the Stability of Proteins from Rates of Oxidation (SPROX) technique, the thermodynamic stabilities of proteins in brain tissue cell lysates from Huα-Syn(A53T) transgenic mice were profiled at three time points including at 1 month (n=9), at 6 months (n=7), and at the time (between 9 and 16 months) a mouse became Symptomatic (n=8).
2021-09-19 | PXD016985 | Pride
Project description:Human iPSC derived dopaminergic neurons were characterized using unbiased single cell transcriptomics. Then study the genetic effect of the A-syn A53T mutation along with oxidative and ER stress induced by rotenone and tunicamycin respectively.
2020-05-29 | E-MTAB-9154 | biostudies-arrayexpress
Project description:The mesencephalic dopaminergic (mDA) cell system is composed by two major groups of projecting cells in the Substantia Nigra (A9 neurons) and the Ventral Tegmental Area (A10 cells). A9 neurons form the nigrostriatal pathway and are involved in regulating voluntary movements and postural reflexes. Their selective degeneration leads to Parkinson’s disease (PD). We used cDNA microarrays and nanoCAGE technology coupled with Laser Capture Microdissection (LCM) to characterize the intrinsic physiological properties of A9 DA neurons. Surprisingly, we found that these cells express alpha- and beta- chains of haemoglobin. Here we report that globin-immunoreactivity decorates the majority of A9 DA neurons, a subpopulation of cortical and hippocampal astrocytes as well as mature oligodendrocytes. This pattern of expression was confirmed in different mouse strains, in rat and human. This is the first report showing that haemoglobin is expressed in the Substantia Nigra of human post mortem brain. Our data suggest that the most famed oxygen-carrying globin is not exclusively restricted to the blood, but it may play a role in the normal physiology of the brain as well as in neurodegenerative disorders.
2009-08-04 | GSE16192 | GEO
Project description: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.
2019-06-25 | GSE131597 | GEO
Project description:The mesencephalic dopaminergic (mDA) cell system is composed by two major groups of projecting cells in the Substantia Nigra (A9 neurons) and the Ventral Tegmental Area (A10 cells). A9 neurons form the nigrostriatal pathway and are involved in regulating voluntary movements and postural reflexes. Their selective degeneration leads to Parkinsons disease (PD). We used cDNA microarrays and nanoCAGE technology coupled with Laser Capture Microdissection (LCM) to characterize the intrinsic physiological properties of A9 DA neurons. Surprisingly, we found that these cells express alpha- and beta- chains of haemoglobin. Here we report that globin-immunoreactivity decorates the majority of A9 DA neurons, a subpopulation of cortical and hippocampal astrocytes as well as mature oligodendrocytes. This pattern of expression was confirmed in different mouse strains, in rat and human. This is the first report showing that haemoglobin is expressed in the Substantia Nigra of human post mortem brain. Our data suggest that the most famed oxygen-carrying globin is not exclusively restricted to the blood, but it may play a role in the normal physiology of the brain as well as in neurodegenerative disorders. To investigate the biological effects of globin expression, alpha- and beta- chains of mouse hemoglobin were overexpressed in MN9D dopaminergic neuroblastoma cell lines. RNA from 4 replicates each of over-expressing cells and of control samples, for a total of 8 samples, were hybridized on Affymetrix GeneChip Mouse Genome 430A 2.0 Arrays. Hybridization of one of the control samples did not pass quality assessment and the sample was therefore excluded from further analysis.
2010-02-25 | E-GEOD-16192 | biostudies-arrayexpress