Single nucleus RNA sequencing data of Lewy Body Dementia (LBD) brains
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA988028 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25043307.fastq.gz | Fastqsanger.gz | |||
| SRR25043308.fastq.gz | Fastqsanger.gz | |||
| SRR25043309.fastq.gz | Fastqsanger.gz | |||
| SRR25043310.fastq.gz | Fastqsanger.gz | |||
| SRR25043311.fastq.gz | Fastqsanger.gz |
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Project description:Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we generated human cortical LBD models by differentiating induced pluripotent stem cells (iPSCs) from SNCA triplication LBD patients into cerebral organoids and observed increased levels of pathological α-SYN in these organoids. Single-cell RNA sequencing revealed prominent expression of the SNCA gene in excitatory neurons, which exhibited synaptic and mitochondrial dysfunction, consistent with findings in the cortex of LBD human brains. Furthermore, screening 1280 FDA-approved drugs identified four candidates, which inhibited α-SYN seeding in RT-QuIC assay, reduced α-SYN aggregation and alleviated mitochondrial dysfunction in SNCA triplication iPSC models. Our findings provide valuable insights into the development of cortical LBD models and the discovery of potential drugs targeting α-SYN aggregation.
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Project description:Recent studies indicate that the adaptive immune system plays a role in Lewy body dementia (LBD). However, the mechanism regulating T cell brain homing in LBD is unknown. Here, we observed T cells adjacent to Lewy bodies and dopaminergic neurons in post-mortem LBD brains. Single-cell RNA sequencing of cerebrospinal fluid (CSF) identified upregulated expression of C-X-C Motif Chemokine Receptor 4 (CXCR4) in CD4+ T cells in LBD. CSF protein levels of the CXCR4 ligand, C-X-C Motif Chemokine Ligand 12 (CXCL12) were associated with neuroaxonal damage in LBD. Furthermore, we observed clonal expansion and upregulated Interleukin 17A expression by CD4+ T cells stimulated with a phosphorylated α-synuclein epitope. Thus, CXCR4-CXCL12 signaling may represent a mechanistic target for inhibiting pathological interleukin-17-producing T cell trafficking in LBD.
2021-09-14 | GSE141578 | GEO
Project description:Recent studies indicate a role of the adaptive immune system in Lewy body dementia (LBD). However, the mechanisms regulating T cell brain homing in LBD remain unknown. Here, we demonstrate interaction of T cells with Lewy bodies and with dopaminergic neurons in post-mortem LBD brains. Single cell RNA sequencing of cerebrospinal fluid (CSF) cells identified upregulated expression of C-X-C Motif Chemokine Receptor 4 (CXCR4) in CD4+ T cells in LBD. CSF protein levels of the CXCR4 ligand, C-X-C Motif Chemokine Ligand 12 (CXCL12) were associated with neuroaxonal damage in LBD. Finally, we demonstrate clonal expansion and upregulated Interleukin 17A by CD4+ T cells stimulated with phosphorylated α-synuclein. Cumulatively, these results indicate CXCR4-CXCL12 signaling as a mechanistic target for inhibiting pathological T cell trafficking in LBD.
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Project description:FAD and Lewy Body Dementia (LBD): Detection of S-Nitrosylation in Key Proteins in Human, Post-mortem Brain Samples
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Project description:CD4+ T cells contribute to neurodegeneration in Lewy body dementia [CSF_and_PBMCs_Healthy and LBD]
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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.
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Project description:CD4+ T cells contribute to neurodgeneration in Lewy Body dementia
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Project description:Mutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD) – collectively Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutation contributes to the susceptibility of developing LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in post-mortem brain tissue from LBD and controls with and without GBA mutations. Our study shows that LBD brains, regardless of GBA mutations, are characterised by altered sphingolipid metabolism, with prominent changes in ceramide species. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD post-mortem CSF and frontal cortex are heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and amyloid precursor protein. Our in vitro studies demonstrate that LBD EV constitute a “pathological package” capable of inducing aggregation of wild type alpha-synuclein, potentially through a combination of alpha-synuclein-ceramide interaction and the presence of pathological forms of alpha-synuclein. Together our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers. GBA mutation likely accelerates the pathological process occurring in sporadic LBD, probably through endolysosomal deficiency, but does not induce alpha-synucleinopathy since healthy normal GBA mutation carriers without alpha-synuclein pathology occur.
2021-11-02 | PXD026980 | Pride
Project description:Dementia with Lewy bodies (DLB) is a common form of dementia with known genetic and environmental interactions. However, the underlying epigenetic mechanisms which reflect these gene-environment interactions are poorly studied. Herein, we measured genome-wide DNA methylation profiles of post-mortem brain tissue (Broadmann area 7) from 15 pathologically confirmed DLB brains and compared them with 16 cognitively normal controls using Illumina MethylationEPIC arrays. We identified 17 significantly differentially methylated CpGs (DMCs) and 17 differentially methylated regions (DMRs) between the groups. The DMCs are mainly located at the CpG islands, promoter and first exon regions. Genes associated with the DMCs are linked to “Parkinson disease” and “metabolic pathway”, as well as the diseases of “severe intellectual disability” and “mood disorders”. Overall, our study highlights previously unreported DMCs offering insights into DLB pathogenesis with the possibility that some of these could be used as biomarkers of DLB in the future.
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Project description:Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of diseasemodifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.
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