Transcriptome of differentiated AST and NAS iPS cell lines to human-like dopamine neurons
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE163344 | GEO | 2021/06/15
REPOSITORIES: GEO
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Project description:Transcriptome of differentiated AST and NAS iPS cell lines to human-like dopamine neurons
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Project description:A major barrier to research on Parkinson’s disease (PD) is inaccessibility of diseased tissue for study. One solution is to derive induced pluripotent stem cells (iPSCs) from patients with PD and differentiate them into neurons affected by disease. We created an iPSC model of PD caused by triplication of SNCA encoding ?-synuclein. ?-Synuclein dysfunction is common to all forms of PD, and SNCA triplication leads to fully penetrant familial PD with accelerated pathogenesis. After differentiation of iPSCs into neurons enriched for midbrain dopaminergic subtypes, those from the patient contain double ?-synuclein protein compared to those from an unaffected relative, precisely recapitulating the cause of PD in these individuals. A measurable biomarker makes this model ideal for drug screening for compounds that reduce levels of ?-synuclein, and for mechanistic experiments to study PD pathogenesis. This SNP microarray study was carried out to confirm presence of SNCA triplication in the affected subject and the derived cell lines. 11 samples were analysed: genomic DNA from the two subjects in the study, the two parent fibroblast lines (AST denoting alpha-synuclein triplication and NAS denoting normal alpha-synuclein), two iPSC lines from each parent fibroblast line (four in total), a human embryonic stem cell line (SHEF4) and two neuronal samples one each from AST and NAS iPSCs).
2011-09-14 | E-GEOD-28366 | biostudies-arrayexpress
Project description:The amygdalostriatal transition zone (ASt) is anatomically poised to provide a shortcut between corticolimbic and basal ganglia circuitry, and mediate behavioral responses to stimuli in parallel with the amygdala. Like the amygdala, the ASt receives converging sensory input from thalamic and cortical pathways. However, the projections of the ASt are distinct from canonical outputs of the amygdala complex, and are integrated with striatal circuits involved in action selection. Despite this intriguing circuit connectivity, the function of the ASt is almost completely unknown. In the present study, we collected cellular resolution recordings of genetically-defined neurons during a valence discrimination task to interrogate the functional role of ASt circuitry, and characterized the transcriptomic profile of the ASt in comparison to neighboring regions. We find that ASt neurons, and specifically, ASt neurons expressing dopamine receptor 2 (D2+), robustly encode sustained conditioned responses to cues of negative valence. Selective inhibition of D2+ ASt neurons was found to cause a striking reduction in conditioned fear responses. We also used single-nucleus RNA sequencing to generate a comprehensive profile of gene expression in ASt neurons, and found that the ASt is genetically distinct from adjacent GABAergic brain regions. RNAscope labelling also confirmed there is a greater proportion of D2+ neurons than D1+ neurons in the ASt, a unique feature compared to other regions of the striatum. Together, our findings provide the first evidence the ASt is a critical structure for encoding learned associations to direct motivated behavior.
2024-04-01 | GSE211437 | GEO
Project description:Dopamine (DA) neurons modulate neural circuits and behaviors via dopamine release from expansive, long range axonal projections. The elaborate cytoarchitecture of DA neurons is embedded within complex brain tissues, making it difficult to access the DA neuronal proteome using conventional methods. Here, we demonstrate APEX2 proximity labeling within genetically targeted neurons in the mouse brain, enabling subcellular proteomics with cell type-specificity. By combining APEX2 biotinylation with mass spectrometry, we mapped the somatodendritic and axonal proteomes of DA neurons. Our dataset reveals the proteomic architecture underlying axonal transport, dopamine transmission, and axonal metabolism in DA neurons. We find a significant enrichment of proteins encoded by Parkinson’s disease-linked genes in dopaminergic axons, including proteins with previously undescribed axonal localization. Our proteomic datasets comprise a significant resource for axonal and DA neuronal cell biology, while the methodology developed here will enable future studies of other neural cell types.
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Project description:Midbrain dopamine neurons project to numerous targets throughout the brain to modulate various behaviors and brain states. Within this small population of neurons exists significant heterogeneity based on physiology, circuitry, and disease susceptibility. Recent studies have shown that dopamine neurons can be subdivided based on gene expression; however, the extent to which genetic markers represent functionally relevant dopaminergic subpopulations has not been fully explored. Here we performed single-cell RNA-sequencing of mouse dopamine neurons and validated studies showing that Neurod6 and Grp are selective markers for dopaminergic subpopulations. Using a combination of multiplex fluorescent in situ hybridization, retrograde labeling, and electrophysiology in mice of both sexes, we defined the anatomy, projection targets, physiological properties, and disease vulnerability of dopamine neurons based on Grp and/or Neurod6 expression. We found that the combinatorial expression of Grp and Neurod6 defines dopaminergic subpopulations with unique features. Grp/Neurod6 dopamine neurons reside in the ventromedial VTA, send projections to the medial shell of the nucleus accumbens, and have noncanonical physiological properties. Grp/Neurod6- DA neurons are found in the VTA as well as in the ventromedial portion of the SNc, where they project selectively to the dorsomedial striatum. Grp-/Neurod6 DA neurons represent a smaller VTA subpopulation, which is preferentially spared in a 6-OHDA model of Parkinson’s disease. Together, our work provides detailed characterization of Neurod6 and Grp expression in the midbrain and generates new insights into how these markers define functionally relevant dopaminergic subpopulations with distinct projection patterns, physiology, and disease vulnerability.
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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:Dopamine acts on neurons in the arcuate nucleus of the hypothalamus (ARC) which control homeostatic feeding responses. Here we demonstrate a differential enrichment of Drd1 expression in food intake-promoting AgRP/NPY neurons and a large proportion of Drd2-expressing anorexigenic POMC neurons. This translates into a predominant activation of AgRP/NPY neurons upon dopamine stimulation and a larger proportion of dopamine-inhibited POMC neurons. Employing intersectional targeting of Drd2-expressing POMC neurons, we reveal, that dopamine-mediated POMC neuron inhibition is Drd2-dependent and that POMCDrd2+ neurons exhibit differential expression of neuropeptide signaling mediators, which manifests in enhanced somatostatin responsiveness of these neurons compared to the global POMC neuron population. Retrograde pseudorabies mapping reveals predominant synaptic input onto these cells from within the ARC as well as characterized dopaminergic cell groups within the hypothalamus and subthalamic areas. Finally, selective chemogenetic activation of POMCDrd2+ neurons uncovers their ability to acutely suppress feeding and to preserve body temperature. Collectively, the present study provides the molecular and functional characterization of POMCDrd2+ neurons and aids to our understanding of dopamine-dependent control of homeostatic energy regulatory neurocircuits.
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Project description:Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD) but neuronal cultures are confounded by cellular heterogeneity. By applying high-resolution single cell transcriptomic analyses to Parkinson’s iPSC-derived dopamine neurons carrying the GBA-N370S risk variant, we exploited intra-culture cellular heterogeneity to identify a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Analysis of genes differentially-expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with compounds known to modulate HDAC4 activity upregulated genes early in the DE axis, and corrected Parkinson’s-related cellular phenotypes. Our study demonstrates how single cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.
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Project description:Ribosome profiling of G2019S LRRK2 human dopamine neurons
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