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PROVIDER: PRJEB52037 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Candidate biomarkers of EV-microRNA in detecting REM sleep behavior disorder and Parkinson’s disease
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Project description:Gut microbiota across early stages of alpha-synucleinopathy
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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
Project description:Acute inflammatory processes disrupt hypothalamic homeostatic systems, leading to a preference for sleep over wakefulness. Orexin knockout mice exhibit faster recovery from LPS-induced sickness, possibly due to enhanced sleep during inflammation. The reduction in orexin activity limits physical activity and encourages sleep, though it remains uncertain whether these responses are pathological or protective. In this study, to investigate the effects of daridorexant, a dual orexin receptor antagonist, on brain inflammation and sleep quality, we employed a systemic inflammatory model in C57BL/6J mice. LPS treatment resulted in significant decreases in REM sleep and wakefulness, while non-REM sleep increased. Here, we provide gene expression profiling of hypothalamus tissues using the RNA sequencing for identifying changes by daridorexant in gene expression of the LPS-treated mice.
2025-02-25 | GSE281503 | GEO
Project description:Microbiota for rapid eye movement sleep behavior disorder
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Project description:The perioculomotor (pIII) region of the midbrain was postulated as a sleep-regulating center in the 1890s but largely neglected in subsequent studies. Using activity-dependent labeling and gene-expression profiling, we identified pIII neurons that promote non-REM (NREM) sleep.
2019-05-01 | GSE124681 | GEO
Project description:The synaptic protein α-synuclein is linked through genetics and neuropathology to the pathogenesis of Parkinson’s disease and related disorders. However, the mechanisms by which α-synuclein influences disease onset and progression are incompletely understood. To identify novel pathways and potential therapeutic targets we performed proteomic analysis in a highly penetrant new Drosophila model of α-synucleinopathy. We identified 476 significantly upregulated and 563 significantly downregulated proteins in heads from α-synucleinopathy model flies compared to controls. We then used multiple complementary analyses to identify and prioritize genes and pathways within the large set of differentially expressed proteins for functional studies. We performed Gene Ontology enrichment analysis, integrated our proteomic changes with human Parkinson’s disease genetic studies, and compared the α-synucleinopathy proteome with that of tauopathy model flies, which are relevant to Alzheimer’s disease and related disorders. These approaches identified GTP cyclohydrolase (GCH1) and folate metabolism as candidate mediators of α-synuclein neurotoxicity. In functional validation studies we found that knockdown of Drosophila Gch1 enhanced locomotor deficits in α-synuclein transgenic flies, while folate supplementation protected from α-synuclein toxicity. Our integrative analysis suggested that mitochondrial dysfunction was a common downstream mediator of neurodegeneration. Accordingly, Gch1 knockdown enhanced metabolic dysfunction in α-synuclein transgenic fly brains while folate supplementation partially normalized whole brain bioenergetics. Here we outline and implement an integrative approach to identify and validate potential therapeutic pathways using comparative proteomics and genetics and capitalizing on the facile genetic and pharmacological tools available in Drosophila.
2021-09-09 | PXD021312 | Pride
Project description:Lewy body disorders are characterized by alpha-synucleinopathic inclusions that tend to develop in neurons extending long, thin, and unmyelinated fibers. It is unknown if this selective vulnerability reflects poor myelination per se. We have observed that preformed fibrils (PFFs) of alpha-synuclein tend to induce pathology in gray matter, even when infused into regions penetrated by white matter bundles. In addition, we found that levels of insoluble, hyperphosphorylated alpha-synuclein correlate inversely with myelin markers in the postmortem amygdala of men—but not women—with Lewy body disease. Thus, we tested if myelin disruption with pharmacologic or genetic tools exacerbates alpha-synucleinopathic lesions in a model of early-stage, limbic Lewy body disease. In genetically outbred CD-1 mice infused with PFFs in the caudal olfactory bulb, the myelin-disruptor cuprizone caused subtle exacerbation of α-synucleinopathy, but without impacting PFF-induced neuron loss or behavior deficits. Furthermore, in C57BL/6J mice heterozygous for myelin basic protein (Mbp+/shi), PFF-induced increases in the insolubility and hyperphosphorylation of alpha-synuclein were not amplified and histological outcomes were not markedly exacerbated. Given our observations of inverse correlations between α-synucleinopathy and myelin markers in the human male amygdala, Lewy body disease may disrupt myelination, rather than poor myelination status regulating the emergence of limbic α-synucleinopathy. This new perspective is reinforced by suppressed expression of select oligodendrocytic markers in the amygdalae of men with Lewy body disease compared to women. Thus, resilient neurons may defy the initial development of Lewy-related pathologies due to properties unrelated to myelination per se.
2025-05-20 | GSE297212 | GEO
Project description:Neurotransmitter release occurs through exocytosis of synaptic vesicles. α-Synuclein’s function and dysfunction in Parkinson’s disease and other synucleinopathies is tightly linked to synaptic vesicle binding. Age is the biggest risk factor for synucleinopathy, and ~15% of synaptic vesicle proteins are linked to diseases of the central nervous system. Yet, age- and disease-induced changes in synaptic vesicles remain unexplored. For an unbiased analysis of the synaptic vesicle proteome, we applied quantitative mass spectrometry to crude synaptic vesicles isolated at three time points (1 month, 3 months, and 10 months of age) from wild-type mice, alpha-synuclein knockout mice, and alpha-synuclein BAC mice, which express human wild-type alpha-synuclein under all human regulatory elements in absence of mouse alpha-synuclein, providing human-like spatiotemporal expression of alpha-synuclein and recapitulating motor and pathological features of Parkinson’s disease. We identified specific changes in synaptic vesicle proteins that capture aging and synucleinopathies. These findings not only provide new insights into synaptic vesicle biology and mechanisms of synucleinopathy, but also offer a baseline for further mechanistic exploration of age- and disease-related alterations in synaptic vesicles.
2025-05-02 | PXD048771 | Pride
Project description:Parkinson’s disease is the second most common neurodegenerative disease. In the vast majority of cases the origin is not genetic and the cause is not well understood, although progressive accumulation of α-synuclein aggregates appears central to the pathogenesis. Currently, treatments that slow disease progression are lacking, and there are no robust biomarkers that can facilitate the development of such treatments or act as aids in early diagnosis. Therefore, we have defined metabolomic changes in the brain and serum in an animal model of prodromal Parkinson’s disease. We biochemically profiled the brain tissue and serum in a mouse model with progressive synucleinopathy propagation in the brain triggered by unilateral injection of preformed α-synuclein fibrils in the olfactory bulb. In total, we accurately identified and quantified 71 metabolites in the brain and 182 in serum using 1H NMR and targeted mass spectrometry, respectively. Using multivariate analysis, we accurately identified which metabolites explain the most variation between cases and controls. Using pathway enrichment analysis, we highlight significantly perturbed biochemical pathways in the brain and correlate these with the progression of the disease. Furthermore, we identified the top six discriminatory metabolites and were able to develop a model capable of identifying animals with the pathology from healthy controls with high accuracy (AUC (95% CI) = 0.861 (0.755–0.968)). Our study highlights the utility of metabolomics in identifying elements of Parkinson’s disease pathogenesis and for the development of early diagnostic biomarkers of the disease. </br></br> NMR assay is reported in the current study MTBLS640. </br> MS assays are reported in MTBLS674. </br><br/> Linked Studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS674' target='_blank'><span class='label label-success'>MTBLS674</span></a>
2019-02-07 | MTBLS640 | MetaboLights