The expression profiling of the early stage of multiple system atrophy model mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129531 | GEO | 2021/06/01
REPOSITORIES: GEO
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Project description:We developed a novel mice model of multiple system atrophy (MSA)-cerebellar type (MSA-C) by over-expression of human mutant α-synuclein (α-syn) in oligodendrocyte using Tet-off system. We identified distinct microglial subpopulations in a novel MSA-C model mice.
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Project description:Multiple system atrophy (MSA) is a fatal rapidly progressive α-synucleinopathy, characterized by prominent α-synuclein accumulation in oligodendrocytes. In this study we investigated mRNA expression in substantia nigra of MSA transgenic mice (Tg(Plp1-SNCA)1Haa) and wild type controls. This forms part of a larger study in which we investigated miRNA-mRNA regulatory network in substantia nagra and striatum of MSA transgenic mice in pre-motor stage of neurodegenration.
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Project description:Aggregated alpha-synuclein (α-syn) is a principal constituent of Lewy bodies (LBs) and glial cytoplasmic inclusions (GCIs) that are observed respectively inside neurons in Parkinson’s disease (PD) and oligodendrocytes in multiple system atrophy (MSA). Yet, the cellular origin, the exact pathophysiological role, and the mechanism of formation of these inclusions remain to be elucidated. It has recently been proposed that pathological α-syn inclusions are capable of eventually causing the demise of the host cell by virtue of the cumulative sequestration of partner proteins and organelles. In particular, the hypothesis of a local cross-seeding of other fibrillization-prone proteins like tau or TDP-43 has also been put forward. The objective of this study was to examine the composition of these inclusions to gain insight into their origin and mechanisms of formation. We submitted sarkosyl-insoluble extracts of post-mortem brain tissue from PD and MSA patients and control subjects to a comparative proteomic analysis to address these points.
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Project description:Aggregated alpha-synuclein (α-syn) is a principal constituent of Lewy bodies (LBs) and glial cytoplasmic inclusions (GCIs) that are observed respectively inside neurons in Parkinson’s disease (PD) and oligodendrocytes in multiple system atrophy (MSA). Yet, the cellular origin, the exact pathophysiological role, and the mechanism of formation of these inclusions remain to be elucidated. It has recently been proposed that pathological α-syn inclusions are capable of eventually causing the demise of the host cell by virtue of the cumulative sequestration of partner proteins and organelles. In particular, the hypothesis of a local cross-seeding of other fibrillization-prone proteins like tau or TDP-43 has also been put forward. The objective of this study was to examine the composition of these inclusions to gain insight into their origin and mechanisms of formation. We submitted total solubilized and sarkosyl-insoluble extracts of post-mortem brain tissue from PD and MSA patients and control subjects to a comparative proteomic analysis to address these points. In parallel, we used proteomics for α-syn quantification in total solubilized brain homogenates and the respective sarkosyl-insoluble pellets as an unbiased validation of our results obtained by immunoblotting of these samples and fractions.
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Project description:As the resident macrophages of the CNS, microglia fulfill manifold functions important for brain development and homeostasis. In the context of neurodegenerative diseases, they are crucial for de- and regenerative as well as immunological processes. The discovery of distinct activation patterns and increased phagocytosis indicated a damaging role of microglia in multiple system atrophy. This devastating, rapidly progressing atypical parkinsonian disorder is characterized by alpha-synuclein accumulation in the cytoplasm of oligodendrocytes. Alpha-synuclein aggregates have been related to myelin loss, severe neurodegeneration, and motor deficits accompanied by a region-specific myeloid immune response. Analyzing the gene expression profile of microglia in a mouse model of multiple system atrophy, MBP29-hα-syn mice, we identified a disease-assoctiated expression profile with an upregulation of the colony-stimulating factor 1 (Csf1). Thus, we hypothesized that targeting the CSF1 receptor using the small-molecule inhibitor PLX5622 reduces myeloid cells and thereby modifies the disease progression and neuropathological phenotype in this mouse model. After validation of a widespread depletion of myeloid cells after CSF1R inhibition, we consequently analyzed the survival, motor functions, neuropathological characteristics, and gene expression of affected brain regions in MBP29-hα-syn mice. Intriguingly, we identified a two-faced outcome comprising (1) an improved survival rate (24%) accompanied by delayed onset of neurological symptoms in contrast to (2) severely impaired motor functions in beam walking, pole test, and RotaRod of PLX5622-treated MBP29-hα-syn mice. Gene expression analysis revealed that PLX5622 reversed myeloid cell activation, however, predominantly reduced the expression of genes related to transsynaptic signaling and signal release. While these transcriptional changes were accompanied by a reduction of dopaminergic neurons in the substantia nigra pars compacta (19%) of PLX5622-treated MBP29-hα-syn mice, an increase of the striatal neuritic density was observed without changes in alpha-synuclein levels or myelin lipids in the forebrain. Together, our findings provide insight into the complex role of myeloid cell depletion in multiple system atrophy by demonstrating a two-faced outcome on the behavioral and neuronal phenotype of MBP29-hα-syn mice. Therefore, it is important to carefully balance the beneficial and adversive effects of CSF1R inhibition in different models of neurodegenerative disorders prior to clinical translation.
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Project description:Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type. We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for β-amyloid related functional classes, including the known Alzheimer’s disease (AD) genes, APP and PSEN1. This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.
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Project description:Althougha-synuclein is implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels ofa-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous a-synuclein was imprinted into synthetic or disease-relevant conformations. We used a-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) or multiple system atrophy (n=5). We found that a 2.5-fold increase in a-synuclein levels in a-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in a-synuclein gene expression. Progressive neuronal loss was observed only in a-synuclein triplication neurons seeded with brain-amplified fibrils. Transcriptomic analysis and isogenic correction of a-synuclein triplication revealed that intraneuronalalpha-synuclein levels solely and sufficiently explained vulnerability to neuronal death
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Project description:Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type. We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for β-amyloid related functional classes, including the known Alzheimer’s disease (AD) genes, APP and PSEN1. This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.
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