Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity [single-cell RNA-Seq]

ABSTRACT: Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity [single-cell RNA-Seq]

PROVIDER: PRJNA661582 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR12595050_1.fastq.gz	Fastqsanger.gz
	SRR12595050_2.fastq.gz	Fastqsanger.gz
	SRR12595051_1.fastq.gz	Fastqsanger.gz
	SRR12595051_2.fastq.gz	Fastqsanger.gz
	SRR12595052_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 8

Similar Datasets

Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity

Project description:Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity

| PRJNA661576 | ENA

Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity [bulk RNA-Seq]

Project description:Increasing evidence from recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson’s disease (PD). Nevertheless, it is currently unknown whether microglia activation could also be a primary event leading to neurodegeneration in PD. We have generated a new mouse model with strictly selective alpha-Synuclein (aSYN) accumulation in microglial cells by inducible gene expression through lentiviral transduction in the nigral tissue. Surprisingly, these mice develop progressive and restricted degeneration of dopaminergic (DA) neurons without any sign of aSYN endogenous aggregation. aSYN accumulating microglial cells exhibit a strong inflammatory status with production of pro-inflammatory cytokines and chemokines. Bulk and scRNA-sequencing of the immune cellular infiltrate identify a complex cellular composition with numerous peripheral populations of the innate and adaptive immune system with specific transcriptional signatures. Molecular profiling and functional assessment reveal that intoxicated microglia develop exhausted phagocytosis and high production of oxidative molecules creating a molecular feed-forward vicious cycle with IFNg secreting immune cells infiltrated in the brain parenchyma. In these animals, pharmacological inhibition of the oxidative and nitrosative molecule production is sufficient to attenuate neurodegeneration. These results suggest that aSYN accumulation in microglia exerts selective DA neuronal degeneration by promoting phagocytic exhaustion, excessive toxic environment and selective recruitment of peripheral immune cells.

2021-09-13 | GSE157533 | GEO

Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity [single-cell RNA-Seq]

2021-09-13 | GSE157534 | GEO

Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity [bulk RNA-Seq]

Project description:Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity [bulk RNA-Seq]

| PRJNA661580 | ENA

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

Project description:Disruption of local iron homeostasis is a common feature of neurodegenerative diseases. We focused on dopaminergic neurons, asking how iron transport proteins modulate iron homeostasis in vivo. Inactivation of the transmembrane iron exporter ferroportin had no apparent consequences. However, loss of the transferrin receptor 1, involved in iron uptake, caused profound, age-progressive neurodegeneration with features similar to Parkinson’s disease. There was gradual loss of dopaminergic projections in the striatum with subsequent death of dopaminergic neurons in the substantia nigra. After depletion of 30% of the neurons the mice developed neurobehavioral parkinsonism, with evidence of mitochondrial dysfunction and impaired mitochondrial autophagy. Molecular analysis revealed strong signatures indicative of attempted axonal regeneration, a metabolic switch to glycolysis and the unfolded protein response. We speculate that cellular iron deficiency may contribute to neurodegeneration in human patients Using Ribotag technology, from mouse ventral midbrain lysates, we isolated actively translated mRNA species from control and Transferrin receptor 1-null dopaminergic neurons. Two mouse ages were used 3 wks (early neurodegeration) 10 wks (late neurodegeneration)

2015-03-11 | E-GEOD-66730 | biostudies-arrayexpress

Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity.

Project description:Recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson's disease. Nevertheless, it is currently unknown whether microglial activation constitutes a primary event in neurodegeneration. We generated a new mouse model by lentiviral-mediated selective α-synuclein (αSYN) accumulation in microglial cells. Surprisingly, these mice developed progressive degeneration of dopaminergic (DA) neurons without endogenous αSYN aggregation. Transcriptomics and functional assessment revealed that αSYN-accumulating microglial cells developed a strong reactive state with phagocytic exhaustion and excessive production of oxidative and proinflammatory molecules. This inflammatory state created a molecular feed-forward vicious cycle between microglia and IFNγ-secreting immune cells infiltrating the brain parenchyma. Pharmacological inhibition of oxidative and nitrosative molecule production was sufficient to attenuate neurodegeneration. These results suggest that αSYN accumulation in microglia induces selective DA neuronal degeneration by promoting phagocytic exhaustion, an excessively toxic environment and the selective recruitment of peripheral immune cells.

| S-EPMC8556263 | biostudies-literature

Phenotypic manifestation of alpha-synuclein strains from Parkinson’s disease and multiple system atrophy in human dopaminergic neruons

Project description:Although α-synucleinis implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of α-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 α-synuclein was imprinted into synthetic or disease-relevant conformations. We used α-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) .We found that a 2.5-fold increase in α-synuclein levels in α-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in α-synuclein gene expression.Transcriptomic analysis and isogenic correction of α-synuclein triplication revealed that intraneuronal α-synuclein levels solely and sufficiently explained vulnerability to cell death.

2020-09-02 | GSE149632 | GEO

Neurodegeneration and Neuroinflammation are Linked, but Independent of α-Synuclein Inclusions, in a Seeding/Spreading Mouse Model of Parkinson’s Disease

Project description:A key process of neurodegeneration in Parkinson's disease (PD) is the transneuronal spreading of alpha-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of a-synuclein particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used spreading/aggregation of alpha-synuclein induced by intracerebral injection of a-synuclein preformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for a-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also withouta-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observed early and unique alterations linked to microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that a-synuclein inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that diffusible, oligomeric a-synuclein species, which induce unusual microglial reactivity, play a key role in this process.

2020-11-02 | GSE155716 | GEO

Phenotypic manifestation of alpha-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons

Project description:Althougha-synuclein is implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels ofa-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 intraneuronalalpha-synuclein levels solely and sufficiently explained vulnerability to neuronal death

2021-04-13 | GSE171999 | GEO

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

2015-03-11 | GSE66730 | GEO