Gene expression profiling of FACS-purified striatal medium spiny neurons in Huntington's disease model mouse
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PROVIDER: PRJNA454479 | ENA |
REPOSITORIES: ENA
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Project description:Gene expression profiling of FACS-purified striatal medium spiny neurons and striatum in Huntington's disease model mouse
| PRJNA454476 | ENA
Project description:Gene expression profiling of purified medium spiny neurons (MSNs) in R6/2 Huntington’s disease (HD) model mouse. To purify MSNs by FACS, R6/2 was crossed with Scn4b-Venus transgenic mouse expressing Venus in MSNs. MSN gene set excluded gene expression alterations in other neuronal populations, indicating the gene set displays MSN-specific pathological changes in HD. We identified the dysregulated genes expression, which are associated with apoptosis and transcriptional regulation, and found considerable number of disease causative genes in MSN gene set.
2020-06-03 | GSE113928 | GEO
Project description:mRNAseq for baseline transcriptional profiling of D1 and D2 receptor-expressing medium spiny neurons from 5-6 month BACHD mice, compared to respective WT littermates. BACHD iSPN and dSPN RNAseq data has been described in "Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease"; Plotkin et al; 2014; PMID accession number 24991961.
2017-08-31 | GSE103341 | GEO
Project description:L-3,4-dihydroxyphenylalanine (levodopa) treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). While it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene expression changes that occur in sub-classes of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes whose expression is correlated with levodopa dose, many of which are under the control of AP-1 and ERK signaling. In spite of homeostatic adaptations involving several signaling modulators, AP-1-dependent gene expression remains highly dysregulated in direct pathway SPNs (dSPNs) upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease. To profile the cell-type-specific responses of striatal spiny projection neurons (SPNs) to striatal dopamine depletion, we conducted TRAP analysis of the two major classes of these neurons: dSPNs that express the dopamine receptor 1a (Drd1a), and iSPNs that express the dopamine receptor 2 (Drd2). To disrupt dopamine innervation to both of these SPN populations that reside in the striatum, we injected the neurotoxin 6-hydroxydopamine (6-OHDA), unilaterally, in the medial forebrain bundle (MFB) in hemizygous Drd1-TRAP and Drd2-TRAP adult (9-14 weeks) male mice (kept on a C57BL/6J genetic background). This lesion procedure causes nigral dopamine cell death within a few days, along with a widespread and near-complete loss of dopaminergic innervation to the entire dorsal striatum on one side of the brain (a hemiparkinsonian model). We first examined the effects of dopamine depletion alone, compared to a mock lesion (ascorbate / saline injected). We then examined the effects of chronic levodopa treatment upon the molecular profiles of dopamine- depleted dSPNs and iSPNs, with two dose regimens. The ‘high-dose’ L-DOPA regimen (3 mg/kg on days 1-3, followed by 6 mg/kg on days 4-9) was expected to induce severe dyskinesia in all MFB-lesioned mice. The low-dose L-DOPA regimen (1 mg/kg on days 1-3, followed by 2 mg/kg on days 4-9) was expected to reverse limb use asymmetry without causing conspicuous dyskinesias. To equalize the effects of stress and handling across all groups, including control groups, all mice were equally handled and thus received saline injections when not receiving levodopa injections. Each treatment group contained 7-10 replicates. TRAP-purified mRNAs from either Drd1a- or Drd2-expressing SPNs were reverse-transcribed, amplified, and used to interrogate Affymetrix 430_2.0 GeneChip microarrays.
2014-03-03 | E-GEOD-55096 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-06-03 | GSE113930 | GEO
Project description:Somatic expansion of the Huntington’s disease (HD) CAG repeat drives the rate of a pathogenic process resulting in neuronal cell death. Although mechanisms of neuronal toxicity are not well delineated, transcriptional dysregulation is a likely contributor. Chromatin modifiers are implicated in both mechanisms of CAG instability and transcriptional dysregulation. Here, we tested whether histone deacetylase genes Hdac2 and Hdac3 modify molecular and cellular phenotypes in HttQ111 knock-in mice using conditional knockouts in striatal medium-spiny striatal neurons (MSNs) exhibiting extensive CAG expansion and exquisite disease vulnerability. MSN-specific Hdac2 or Hdac3 knockout attenuated CAG expansion, with the Hdac2 knockout impacting nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included reversal of transcriptional dysregulation elicited by the HttQ111 allele. Our results identify novel modifiers of CAG expansion in MSNs, providing testable mechanistic hypotheses, and a potentially complex relationship between Htt and Hdac2 with implications for targeting transcriptional dysregulation in HD.
2020-06-01 | GSE148440 | GEO
Project description:L-3,4-dihydroxyphenylalanine (levodopa) treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). While it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene expression changes that occur in sub-classes of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes whose expression is correlated with levodopa dose, many of which are under the control of AP-1 and ERK signaling. In spite of homeostatic adaptations involving several signaling modulators, AP-1-dependent gene expression remains highly dysregulated in direct pathway SPNs (dSPNs) upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease.
2014-03-03 | GSE55096 | GEO
Project description:3 subtypes of cortical projection neurons were purified by fluorescence-activated cell sorting at 4 different stages of development from mouse cortex. A detailed description of the data set is described in Arlotta, P et al (2005). Keywords = corticospinal motor neuron callosal corticotectal cortex development FACS
2005-01-19 | GSE2039 | GEO
Project description:Background Proteomic characterization of microglia has been limited by low yield and contamination by non-microglial proteins by magnetic-activated cell sorting (MACS) enrichment strategies. To determine whether a fluorescent-activated cell sorting (FACS)-based strategy overcomes these limitations, we compared microglial proteomes of MACS and FACS-based purified CD11b+ microglia in order to identify core sets of microglial proteins in adult mouse brain tissue. Results Quantitative multiplex proteomics by tandem mass tag mass spectrometry (TMT-MS) of MACS-enriched (N = 5) and FACS-purified (N = 5) adult wild-type CD11b+ microglia identified 1,791 proteins, of which 953 were differentially expressed indicating significant differences between both approaches. While the FACS-purified microglia proteome was enriched with cytosolic, endoplasmic reticulum and ribosomal proteins involved in protein metabolism and immune system functions, the MACS-enriched microglia proteome was enriched with proteins related to mitochondrial function and synaptic transmission. As compared to MACS, the FACS microglial proteome showed strong enrichment for canonical microglial proteins while neuron, astrocyte, and oligodendrocyte proteins were decreased. Interestingly, we observed enrichment of endothelial specific proteins in the FACS microglia proteome. By comparing FACS-purified microglia proteomes with transcriptomes, we observed highly concordant as well as highly discordant proteins that were abundant at the protein level but low at the transcript level. Conclusions We demonstrate that TMT-MS proteomics of FACS-purified adult microglia is superior to column-based enrichment approaches, resulting in purer and highly-enriched microglial proteomes. We also define core sets of highly-abundant adult microglial proteins including Moesin (Msn) that can guide future studies.
2020-05-11 | PXD015652 | Pride
Project description:Molecular and cellular consequences of genetic knockout of Hdac2 and Hdac3 in striatal medium spiny neurons of Huntington's disease knock-in mice
| PRJNA624273 | ENA