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Gene expression profiling of FACS-purified striatal medium spiny neurons and striatum in Huntington's disease model mouse

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE113930 | GEO | 2020/06/03

REPOSITORIES: GEO

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Gene expression profiling of FACS-purified striatal medium spiny neurons in Huntington's disease model mouse

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

Gene expression profiling of FACS-purified striatal medium spiny neurons and striatum in Huntington's disease model mouse

Project description:Gene expression profiling of FACS-purified striatal medium spiny neurons and striatum in Huntington's disease model mouse

| PRJNA454476 | ENA

Gene expression profiling of FACS-purified striatal medium spiny neurons in Huntington's disease model mouse

Project description:Gene expression profiling of FACS-purified striatal medium spiny neurons in Huntington's disease model mouse

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FACS-array-based cell purification yields a specific transcriptome of striatal medium spiny neurons in a murine Huntington disease model.

Project description:Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin gene. Results from previous studies have suggested that transcriptional dysregulation is one of the key mechanisms underlying striatal medium spiny neuron (MSN) degeneration in HD. However, some of the critical genes involved in HD etiology or pathology could be masked in a common expression profiling assay because of contamination with non-MSN cells. To gain insight into the MSN-specific gene expression changes in presymptomatic R6/2 mice, a common HD mouse model, here we used a transgenic fluorescent protein marker of MSNs for purification via FACS before profiling gene expression with gene microarrays and compared the results of this "FACS-array" with those obtained with homogenized striatal samples (STR-array). We identified hundreds of differentially expressed genes (DEGs) and enhanced detection of MSN-specific DEGs by comparing the results of the FACS-array with those of the STR-array. The gene sets obtained included genes ubiquitously expressed in both MSNs and non-MSN cells of the brain and associated with transcriptional regulation and DNA damage responses. We proposed that the comparative gene expression approach using the FACS-array may be useful for uncovering the gene cascades affected in MSNs during HD pathogenesis.

| S-EPMC7380199 | biostudies-literature

The difficulty to model Huntington's disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells.

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.

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Dichotomous anatomical properties of adult striatal medium spiny neurons.

Project description:Principal medium spiny projection neurons (MSNs) of the striatum have long been thought to be homogeneous in their somatodendritic morphology and physiology. Recent work using transgenic mice, in which the two major classes of MSN are labeled, has challenged this assumption. To explore the basis for this difference, D(1) and D(2) receptor-expressing MSNs (D(1) and D(2) MSNs) in brain slices from adult transgenic mice were characterized electrophysiologically and anatomically. These studies revealed that D(1) MSNs were less excitable than D(2) MSNs over a broad range of developmental time points. Although M(1) muscarinic receptor signaling was a factor, it was not sufficient to explain the dichotomy between D(1) and D(2) MSNs. Reconstructions of biocytin-filled MSNs revealed that the physiological divergence was paralleled by a divergence in total dendritic area. Experimentally grounded simulations suggested that the dichotomy in MSN dendritic area was a major contributor to the dichotomy in electrophysiological properties. Thus, rather than being an intrinsically homogenous population, striatal MSNs have dichotomous somatodendritic properties that mirror differences in their network connections and biochemistry.

| S-EPMC3235748 | biostudies-literature

RNAseq of FACS Drd1 and Drd2 receptor expressing medium spiny neurons (direct and indirect medium spiny neurons) from 5-6 month Q175 Huntington's disease model mice, compared to WT littermates.

Project description:mRNAseq for baseline transcriptional profiling of D1 and D2 receptor-expressing medium spiny neurons from 5-6 month Q175 mice compared to WT littermates.

2018-09-01 | GSE103345 | GEO

RNAseq of FACS Drd1 and Drd2 receptor expressing medium spiny neurons (direct and indirect medium spiny neurons) from 5-6 month BACHD Huntington's disease model mice, compared to WT littermates

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

Huntington's disease and the striatal medium spiny neuron: cell-autonomous and non-cell-autonomous mechanisms of disease.

Project description:Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is > 40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum.

| S-EPMC3337013 | biostudies-literature

AAV-dominant negative tumor necrosis factor (DN-TNF) gene transfer to the striatum does not rescue medium spiny neurons in the YAC128 mouse model of Huntington's disease.

Project description:CNS inflammation is a hallmark of neurodegenerative disease, and recent studies suggest that the inflammatory response may contribute to neuronal demise. In particular, increased tumor necrosis factor (TNF) signaling is implicated in the pathology of both Parkinson's disease (PD) and Alzheimer's disease (AD). We have previously shown that localized gene delivery of dominant negative TNF to the degenerating brain region can limit pathology in animal models of PD and AD. TNF is upregulated in Huntington's disease (HD), like in PD and AD, but it is unknown whether TNF signaling contributes to neuronal degeneration in HD. We used in vivo gene delivery to test whether selective reduction of soluble TNF signaling could attenuate medium spiny neuron (MSN) degeneration in the YAC128 transgenic (TG) mouse model of Huntington's disease (HD). AAV vectors encoding cDNA for dominant-negative tumor necrosis factor (DN-TNF) or GFP (control) were injected into the striatum of young adult wild type WT and YAC128 TG mice and achieved 30-50% target coverage. Expression of dominant negative TNF protein was confirmed immunohistologically and biochemically and was maintained as mice aged to one year, but declined significantly over time. However, the extent of striatal DN-TNF gene transfer achieved in our studies was not sufficient to achieve robust effects on neuroinflammation, rescue degenerating MSNs or improve motor function in treated mice. Our findings suggest that alternative drug delivery strategies should be explored to determine whether greater target coverage by DN-TNF protein might afford some level of neuroprotection against HD-like pathology and/or that soluble TNF signaling may not be the primary driver of striatal neuroinflammation and MSN loss in YAC128 TG mice.

| S-EPMC4019512 | biostudies-literature

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