Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Spatial Multi-Omics Identifies Early Synaptic Pruning and Context-Specific Dopaminergic Vulnerability in Synucleinopathies

ABSTRACT: Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer’s disease (AD), and AD with Lewy body pathology (AD+LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: Karsten Nalbach

LAB HEAD: Stefan Lichtenthaler

PROVIDER: PXD062998 | Pride | 2026-06-09

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	AGTK_2403_10-1-B_Slot1-23_1_13666.d.zip	Other
	AGTK_2403_10-2-B_Slot1-24_1_13667.d.zip	Other
	AGTK_2403_11-1-B_Slot1-25_1_13668.d.zip	Other
	AGTK_2403_11-2-B_Slot1-26_1_13669.d.zip	Other
	AGTK_2403_12-1-B_Slot1-27_1_13670.d.zip	Other

Items per page:

1 - 5 of 78

Similar Datasets

Genome-wide transcriptome profiling Brain-Chip and Conventional Cell Culture System Using RNA-seq

Project description:The goal of this study was A) to compare the global RNA-sequencing (RNA-seq) profiles data of the neurovascular units constructed in i) conventional cell cultures (n=4), ii) Substantia Nigra Brain-Chips cultured under constant flow (n=4), and iii) human adult brain-derived substantia nigra (n=8) retrieved from the Genotype-Tissue Expression (GTEx) Portal, B) to identify differences in the transcriptome profiles in brain endothelial cells between the two conditions, αSyn fibrils and αSyn monomers.

2021-09-10 | GSE168870 | GEO

CYP46A1 promotes Parkinson’s disease

Project description:Parkinson’s disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of α-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of α-Syn via the XBP1‒LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD.

2025-01-23 | MTBLS11709 | MetaboLights

Differential Neuropathology, Genetics, and Transcriptomics in two kindred cases with Alzheimer’s Disease and Lewy Body Dementia

Project description:Alzheimer’s disease (AD) and Lewy body dementia (LBD) are two different forms of dementia but their pathology may involve the same cortical areas with overlapping cognitive manifestation. Dementia cases within the same family share a common genetic background. Nonetheless, the clinical phenotype may be different due to the different underlying molecular processes that come-up apart from genetics, causing diverse neurodegeneration. Through neuropathological, genetic and transcriptomic comparison of four different brain areas (substantia nigra, hippocampus, parietal lobe and basal ganglia), we defined commonalities and differences in the pathological processes of dementia in two kindred cases, a mother and a son, who developed a classical AD and an aggressive form of AD/LBD respectively. Genetic analysis did not reveal any pathogenic variants in the principal AD/LBD-causative genes. RNA sequencing highlighted high transcriptional dysregulation within the substantia nigra in LBD pathology, while AD underwent lower degree of transcriptional dysregulation, with the parietal lobe being the most involved brain area. Conversely, hippocampus (the most degenerated area) and basal ganglia (lacking specific lesions) expressed the lowest level of dysregulation. Our data suggest that there is a link between the transcriptional dysregulation and the amount of tissue damage accumulated across time, assessed through neuropathology. Moreover, we highlight that the molecular bases of AD and LBD follow very different pathways, which underlie their neuropathological signatures. Indeed, the transcriptome profiling through RNA sequencing may be an important tool in flanking the neuropathological analysis for a deeper understanding of AD and LBD pathogenesis.

2022-08-03 | GSE193438 | GEO

Systematic meta-analysis and replication of genome-wide expression studies of Parkinson’s disease: 4

Project description:Analysis of substantia nigra from postmortem brains of 4 patients with Parkinson’s disease (PD). Results provide insight into the molecular processes perturbed in the PD substantia nigra.

2011-01-20 | GSE20314 | GEO

System-based analyses of brain regions functionally impacted in Parkinson's disease reveals underlying causal mechanisms

Project description:Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum and cortex are functionally connected with increasing degrees of alpha-synuclein pathology in Parkinson's disease. Functional and causal pathway analysis of gene expression and proteomic alterations in these three regions revealed pathways that correlated with deposition of alpha-synuclein. Microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release and other changes were reflected across all brain regions. Importantly a subset of these changes were replicated in Parkinson's disease blood. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene gene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changes that accompany alpha-synculein pathology in Parkinson's disease, and may be instrumental in understanding and diagnosing Parkinson's disease progression. Substantia Nigra (3 normal, 3 PD), Striatum (6 normal, 6 PD), Cortex (5 normal, 5 PD), Cortex non-PD neurodegeneration (2 normal, 3 DLB). Note Sample X201264 was used both for Cortex normal and for Cortex nonPD normal

2014-09-01 | E-GEOD-54282 | biostudies-arrayexpress

Proteomic characterization of synaptosomes from human substantia nigra indicates altered mitochondrial translation in Parkinson’s disease

Project description:Parkinson´s disease (PD) feature a progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Additionally, numerous studies indicate an altered synaptic function during the course of PD. In order to characterize the proteome of synaptosomes isolated from the substantia nigra and to gain new insights into the molecular processes underlying the alteration of synaptic function in PD, a proteomic study was conducted. Synaptosomes were isolated from substantia nigra tissue of control subjects free of pathology (N = 5) and individuals at advanced PD stages (N = 5) by density gradient centrifugation and further analyzed by mass spectrometry. 362 proteins were identified and assigned to the synaptosomal core proteome. This core proteome includes all proteins expressed within the synapses without regards to data analysis software, gender, age or disease. The CD9 antigen was overrepresented and fourteen proteins, among them Thymidine kinase 2 (TK2), mitochondrial, 39S ribosomal protein L37, mitochondrial,, Neurolysin, and Methionine-tRNA ligase, mitochondrial (MARS2)) were underrepresented suggesting an alteration in mitochondrial translation in PD synaptosomes.

2021-06-07 | PXD022092 | Pride

Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson’s disease

Project description:Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson’s disease and forms inclusions in neurons called Lewy Bodies. While the mechanism underlying the dysregulation of αSyn in Parkinson’s disease is unclear, it is thought that prionoid cell-to-cell propagation of αSyn has an important role. Through a high throughput screen, we recently identified 38 genes whose knock down modulates αSyn propagation. Follow up experiments were undertaken for two of those genes, TAX1BP1 and ADAMTS19, to study the mechanism with which they regulate αSyn homeostasis. We used a recently developed M17D neuroblastoma cell line expressing triple mutant (E35K+E46K+E61K) “3k” αSyn under doxycycline induction. 3k αSyn spontaneously forms inclusions that show ultrastructural similarities to Lewy Bodies. Experiments using that cell line showed that TAX1BP1 and ADAMTS19 regulate how αSyn interacts with lipids and phase separates into inclusions, respectively, adding to the growing body of evidence implicating those processes in Parkinson’s disease. Through RNA sequencing, we identified several genes that are differentially expressed after knock-down of TAX1BP1 or ADAMTS19. Burden analysis revealed that those differentially expressed genes (DEGs) carry an increased frequency of rare risk variants in Parkinson’s disease patients versus healthy controls, an effect that was independently replicated across two separate cohorts (GP2 and AMP-PD). Weighted gene co-expression network analysis (WGCNA) showed that the DEGs cluster within modules in regions of the brain that develop high degrees of αSyn pathology (basal ganglia, cortex). We propose a novel model for the genetic architecture of sporadic Parkinson’s disease: increased burden of risk variants across genetic networks dysregulates pathways underlying αSyn homeostasis, thereby leading to pathology and neurodegeneration.

2025-02-17 | GSE276032 | GEO

Proteomic Profiling of the Substantia Nigra to Identify Determinants of Lewy Body Pathology and Dopaminergic Neuronal Loss

Project description:Proteinaceous aggregates containing alpha-synuclein protein called Lewy bodies in the substantia nigra is a hallmark of Parkinson's disease. The molecular mechanisms of Lewy body formation and associated neuronal loss remain largely unknown. To gain insights on proteins and pathways associated with Lewy body pathology, we performed quantitative profiling of the proteome. We analyzed substantia nigra tissue from 51 subjects arranged into three groups: cases with Lewy body pathology, Lewy body-negative controls with matching neuronal loss and controls with no neuronal loss. Using label-free LC-MS/MS approach we quantified the 2,963 most abundant proteins. Statistical testing for differential protein abundance, followed by pathway enrichment and Bayesian learning of the causal network structure were performed to identify likely drivers of Lewy body formation and dopaminergic neuronal loss. The identified pathways include (1) Arp2/3 complex-mediated actin nucleation; (2) synaptic function; (3) poly(A) RNA binding; (4) basement membrane and endothelium; and (5) hydrogen peroxide metabolic process. According to the data, the endothelial/basement membrane pathway is tightly connected with both pathologies and likely to be one of the drivers of the neuronal loss. The poly(A) RNA-binding proteins, including the ones relevant to other neurodegenerative disorders (e.g. TDP-43 and FUS) have strong inverse correlation with Lewy bodies and may reflect alternative mechanism of nigral neurodegeneration.

2022-08-11 | PXD019279 | Pride

Homo sapiens

Project description:Evidence for immune response, axonal dysfunction and reduced endocytosis preceding Lewy body pathology in the substantia nigra in Parkinson’s disease

| PRJNA212736 | ENA

Systematic meta-analysis and replication of genome-wide expression studies of Parkinson's disease: 1

Project description:Systematic meta-analysis and replication of genome-wide expression studies identifies molecular pathways of Parkinson’s disease. Snap-frozen human substantia nigras (SNs) of 16 individuals with a clinicopathological diagnosis of incidental Lewy body (ILB) disease with Lewy bodies detected in the brainstem nuclei of locus coeruleus and substantia nigra, but generally not in higher cortical regions consistent with Braak stage 3 criteria for Parkinson's disease (PD), and 17 age-, sex-, postmortem interval-, and RNA integrity number-matched controls, who were clinicopathologically within normal limits for age collected under the rapid-autopsy program of Sun Health Research Institute or by the Harvard Brain Tissue Resource Center at McLean Hospital, were used for gene expression analyses in stage 2. Protocols were approved by the Institutional Review Board of Brigham and Women’s Hospital.

2011-01-20 | GSE20159 | GEO