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Investigation in the cannabigerol derivative VCE-003.2 as a disease- modifying agent in a mouse model of experimental synucleinopathy

ABSTRACT: Investigation in the cannabigerol derivative VCE-003.2 as a disease- modifying agent in a mouse model of experimental synucleinopathy

PROVIDER: PRJEB72409 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR12644959.fastq.gz	Fastqsanger.gz
	ERR12644960.fastq.gz	Fastqsanger.gz
	ERR12644961.fastq.gz	Fastqsanger.gz
	ERR12644962.fastq.gz	Fastqsanger.gz
	ERR12644963.fastq.gz	Fastqsanger.gz

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Investigation in the cannabigerol derivative VCE-003.2 as a disease- modifying agent in a mouse model of experimental synucleinopathy

Project description:Here we explore the striatum transcriptomic effects of alpha-synuclein administration in mice as model of Parkinson´s disease. Moreover, we also explore the neuroprotective effect of cannabonoid-based druga (VCE-003.2) as a potential neuroportective agent in Parkinson´s disease

2024-11-30 | E-MTAB-13768 | biostudies-arrayexpress

Investigation in the cannabigerol derivative VCE-003.2 as a disease-modifying agent in a mouse model of experimental synucleinopathy.

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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

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.

2023-06-30 | GSE205511 | GEO

Molecular and functional features of synucleinopathy-associated astrocytes

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Intestinal Macrophages Modulate Brain Synucleinopathy in Parkinson’s Disease

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Stratification Tools for Disease-Modifying Trials in Prodromal Synucleinopathy.

Project description: Not available

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Spatial transcriptomics links hippocampal synaptic remodeling to microglial phagocytosis in synucleinopathy

Project description:Synucleinopathies, including Parkinson’s disease and Lewy body dementia, show region-specific vulnerability across the brain, but the molecular basis of selective regional involvement remains incompletely understood. We performed spatial transcriptomic profiling of brain sections from 6-month-old G2-3 alpha-synuclein transgenic mice and wild-type littermates using the 10x Genomics Visium Spatial Gene Expression platform to characterize region-specific transcriptional alterations associated with alpha-synuclein pathology. This dataset provides a resource for investigating spatially resolved molecular changes in the synucleinopathy mouse brain.

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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

Development of early-stage alpha-synucleinopathy is not governed by myelin status in mice of either sex

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.

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