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Transcriptomic Profiling of Early Synucleinopathy in Rats Induced with Preformed Fibrils

ABSTRACT: Transcriptomic Profiling of Early Synucleinopathy in Rats Induced with Preformed Fibrils

PROVIDER: PRJNA1031579 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26499810_1.fastq.gz	Fastqsanger.gz
	SRR26499810_2.fastq.gz	Fastqsanger.gz
	SRR26499811_1.fastq.gz	Fastqsanger.gz
	SRR26499811_2.fastq.gz	Fastqsanger.gz
	SRR26499812_1.fastq.gz	Fastqsanger.gz

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Transcriptomic Profiling of Early Synucleinopathy in Rats Induced with Preformed Fibrils

Project description:Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-synuclein (α-syn) preformed fibril (PFF) model induces synchronized synucleinopathy that recapitulates the pathological features of Parkinson’s disease (PD) and can be used to study synucleinopathy progression. In this model, phosphorylated α-syn (pSyn) inclusion-containing neurons and reactive microglia (major histocompatibility complex-II immunoreactive) peak in the substantia nigra pars compacta (SNpc) months before appreciable neurodegeneration. However, it remains unclear which specific genes are driving these phenotypic changes. To identify transcriptional changes associated with early synucleinopathy, we used laser capture microdissection of the SNpc paired with RNA sequencing (RNASeq). Precision collection of the SNpc allowed for the assessment of differential transcript expression in the nigral dopamine neurons and proximal glia. Transcripts upregulated in early synucleinopathy were mainly associated with an immune response, whereas transcripts downregulated were associated with neurotransmission and the dopamine pathway. A subset of 29 transcripts associated with neurotransmission/vesicular release and the dopamine pathway were verified in a separate cohort of males and females to confirm reproducibility. Within this subset, fluorescent in situ hybridization (FISH) was used to localize decreases in the Syt1 and Slc6a3 transcripts to pSyn inclusion-containing neurons. Identification of transcriptional changes in early synucleinopathy provides insight into the molecular mechanisms driving neurodegeneration.

2023-10-24 | GSE246112 | GEO

Uptake of alpha-synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia

Project description:To detect the microglial mRNA signature whilst phagocytosing alphasynuclein preformed fibrils (αSyn PFFs) with or without inflammatory stimulus, we treated the healthy control microglia with IFNγ (20ng/ml) 28h and αSyn PFFs (0.5µM) 4h

2024-10-22 | GSE277636 | GEO

RNAseq analysis of primary astrocyte and microglia under Aβ40WT and Aβ42WT fibrils treatment

Project description:To investigate the influence of Aβ40WT and Aβ42WT fibrils on astrocyte and microglia, we isolated astrocyte and microglia from P2 SD rats and treated glia cells with Aβ40WT and Aβ42WT fibrils for 24 hours. We then performed gene expression profiling analysis using data obtained from RNA-seq of astrocyte and microglia treated with Aβ fibrils.

2022-08-17 | GSE211198 | GEO

Molecular and functional features of synucleinopathy-associated astrocytes

Project description:Astrocyte (AC) involvement is a common neuropathological feature in human synucleinopathy-associated neurodegeneration. However, our understanding of the in vivo characteristics of reactive ACs in synucleinopathy remained limited. Here we report the transcriptomic and functional features of a unique synucleinopathy-associated AC (SAA) subtype in a mouse model. SAAs share a convergent transcriptomic state across synucleinopathy-laden brain regions, and are at least partially reliant on microglia for their phenotypic maintenance in vivo. Intravital imaging revealed that an upregulation of the excitatory amino acid transporter 2 (EAAT2) in synucleinopathy-affected ACs is associated with depressed neuronal activities. This is potentially mediated via increased AC glutamate uptake, as pharmacological induction of EAAT2 reproduced the same effect. With cross-species comparative analysis, we showed that the core SAA transcriptomic features are present in human aged and synucleinopathy-affected midbrain ACs, while important distinct characteristics also exist. Collectively, our results uncovered complex reactive AC changes that likely play important adaptive roles in synucleinopathy.

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Modeling α-Synucleinopathy in Organotypic Brain Slice Culture with Preformed α-Synuclein Amyloid Fibrils.

Project description:BackgroundSynucleinopathy is a group of neurodegenerative disorders characterized by neurodegeneration and accumulation of alpha-synuclein (α-syn) aggregates in various brain regions. The detailed mechanism of α-syn-caused neurotoxicity remains obscure, which is partly due to the lack of a suitable model that retains the in vivo three-dimensional cellular network and allows a convenient dissection of the neurotoxic pathways. Recent studies revealed that the pre-formed recombinant α-syn amyloid fibrils (PFFs) induce a robust accumulation of pathogenic α-syn species in cultured cells and animals.ObjectiveOur goal is to determine whether PFFs are able to induce the pathogenic α-syn accumulation and neurotoxicity in organotypic brain slice culture, an ex vivo system that retains the in vivo three-dimensional cell-cell connections.Methods/resultsAdding PFFs to cultured wild-type rat or mouse brain slices induced a time-dependent accumulation of pathogenic α-syn species, which was indicated by α-syn phosphorylated at serine 129 (pα-syn). The PFF-induced pα-syn was abolished in brain slices prepared from α-syn null mice, suggesting that the pα-syn is from the phosphorylation of endogenous α-syn. Human PFFs also induced pα-syn in brain slices prepared from mice expressing human α-syn on a mouse α-syn-null background. Furthermore, the synaptophysin immunoreactivity was inversely associated with pα-syn accumulation and an increase of neuronal loss was detected.ConclusionPFF-treatment of brain slices is able to induce key pathological features of synucleinopathy: pα-syn accumulation and neurotoxicity. This model will be useful for investigating the neurotoxic mechanism and evaluating efficacy of therapeutic approaches.

| S-EPMC7683096 | biostudies-literature

Uptake of alpha-synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia

Project description:Uptake of alpha-synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia

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Synaptic phosphoproteome modifications and cortical circuit dysfunction are linked to the early-stage progression of alpha-synuclein pathology

Project description:Lewy body inclusions enriched with aggregated forms of the presynaptic protein alpha-synuclein (aSyn) are a hallmark of synucleinopathy diseases such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). To model this pathology, C57 mice were injected in the cortex or striatum with preformed fibrils (PFFs) prepared from mouse aSyn to induce the aggregation of the endogenous mouse protein. Monomeric aSyn was injected as a control. Aggregated aSyn was detected via immunohistochemical staining in the sensorimotor cortex at 1- and 3-months post-injection in PFF-injected mice, but not monomer-injected animals. Phosphoproteomics analysis was carried out on homogenates from the sensorimotor cortex of mice inoculated with PFFs or monomer, 3 months post-injection, and the data are presented here.

2024-11-25 | PXD058091 | Pride

Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal α-synuclein preformed fibrils.

Project description:Animal models that accurately recapitulate the accumulation of alpha-synuclein (α-syn) inclusions, progressive neurodegeneration of the nigrostriatal system and motor deficits can be useful tools for Parkinson's disease (PD) research. The preformed fibril (PFF) synucleinopathy model in rodents generally displays these PD-relevant features, however, the magnitude and predictability of these events is far from established. We therefore sought to optimize the magnitude of α-syn accumulation and nigrostriatal degeneration, and to understand the time course of both. Rats were injected unilaterally with different quantities of α-syn PFFs (8 or 16 μg of total protein) into striatal sites selected to concentrate α-syn inclusion formation in the substantia nigra pars compacta (SNpc). Rats displayed an α-syn PFF quantity-dependent increase in the magnitude of ipsilateral SNpc inclusion formation at 2 months and bilateral loss of nigral dopamine neurons at 6 months. Unilateral 16 μg PFF injection also resulted in modest sensorimotor deficits in forelimb adjusting steps associated with degeneration at 6 months. Bilateral injection of 16 μg α-syn PFFs resulted in symmetric bilateral degeneration equivalent to the ipsilateral nigral degeneration observed following unilateral 16 μg PFF injection (~50% loss). Bilateral PFF injections additionally resulted in alterations in several gait analysis parameters. These α-syn PFF parameters can be applied to generate a reproducible synucleinopathy model in rats with which to study pathogenic mechanisms and vet potential disease-modifying therapies.

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RNA-seq analysis for mRNA expression change in alpha-synclein fibril-treated cultured oligodendrocyte precursor cells

Project description:Glial cytoplasmic inclusion is the pathological hallmark of multiple system atrophy commonly observed as alpha-synulcien-positive aggregates within oligodendrocytes. We elucidated that preformed alpha-synulcien fibrils triggers multimerization and upsurge of endogenous alpha-synulcien in oligodendrocyte precursor cells which is attributable to insufficient autophagic proteolysis. To assess the functional influence of alpha-synuclein fibrils application on oligodendrocyte precursor cells, RNA-seq analysis was performed. The data revealed that alpha-synulcien fibrils interfered with numerous protein expressions associated with neuronal support and myelination.

2017-12-02 | GSE107582 | GEO

Molecular and functional features of synucleinopathy-associated astrocytes

Project description:Molecular and functional features of synucleinopathy-associated astrocytes

| PRJNA846176 | ENA