Caenorhabditis elegans
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA622398 | ENA |
REPOSITORIES: ENA
Similar Datasets
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:Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that is characterized by the selective loss of midbrain dopamine (DA)-producing neurons and the formation of α-synuclein (α-syn)-containing inclusions named Lewy bodies (LBs). Here, we report that the loss of glucocerebrosidase (GCase), coupled with α-syn overexpression, result in substantial accumulation of detergent-resistant α-syn aggregates and Lewy body-like inclusions (LBLIs) in human midbrain-like organoids (hMLOs). These LBLIs exhibit a highly similar structure to PD-associated LBs, by displaying a spherically symmetric morphology with an eosinophilic core, and containing α-syn and ubiquitin. Importantly, hMLOs generated from PD patient-derived inducible pluripotent stem cells (iPSCs) harboring SNCA triplication also exhibit subsequent degeneration of DA neurons and LBLI formation upon chronic GCase inhibitor treatment. Taken together, our hMLOs harbouring two major PD risk factors (GCase deficiency and overproduced α-syn) successfully recapitulate major pathophysiological signatures of the disease, and highlight the broad utility of brain organoid technology in modeling human neurodegenerative diseases.
2021-08-13 | E-MTAB-7302 | biostudies-arrayexpress
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.
2021-09-14 | GSE161192 | GEO
Project description:Aggregation of α-synuclein may trigger the development of synucleinopathies, a progressive neurodegenerative disease such as Parkinson's disease and Dementia with Lewy bodies. We demonstrate RNA initiates α-synuclein phase transition in vitro, however, RNA binding ability and its motif remain unclear. Here, we indicate purified human α-synuclein protein preferentially binds to guanine-rich RNA sequences by RNA Bind-N-Seq using a pool of random 24-mer RNA oligonucleotides in vitro. Importantly, these hit motifs were required consecutive guanines not random, suggesting that RNA G-quadruplexes binds to α-synuclein. We also confirmed that GC content and skew of α-synuclein-enriched RNA sequences were similar to that of BG4 (G-quadruplex antibody)-enriched RNA sequences. Taken together, these data suggest that α-synuclein binds to RNA-formed G-quadruplex.
2023-07-17 | GSE235418 | GEO
Project description:SNCA, the first gene associated with Parkinson’s disease, encodes the α-synuclein protein, the predominant component within pathological inclusions termed Lewy bodies. We use 3D midbrain organoids, differentiated from human induced pluripotent stem cells derived from patients carrying a triplication of the SNCA gene and from CRISPR/Cas9 corrected isogenic control iPSCs. These human midbrain organoids recapitulate key features of α-synuclein pathology observed in the brains of patients with synucleinopathies. We used single cell RNA sequencing to characterize the cell types within these organoids. We find an equal proportion of neuronal and glial cells. The neuronal populations consist of dopmainergic, excitatory and inhibitory neurons in early and late stages of maturation as well as neural precursor cells. The glial populations consist of dividing radial glia, radial glia, astrocytes and early oligodendorcytes.
2021-11-02 | GSE186780 | GEO
Project description:CD4+ T cells contribute to neurodgeneration in Lewy Body dementia
| PRJNA675845 | ENA
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.
2021-08-15 | GSE178146 | GEO
Project description:FAD and Lewy Body Dementia (LBD): Detection of S-Nitrosylation in Key Proteins in Human, Post-mortem Brain Samples
2023-03-10 | PXD020945 | Pride
Project description:Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril comprised of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or a-synuclein protein. A combination of cryo-electron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 A from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, N=8), progressive supranuclear palsy (PSP, N=2), or dementia with Lewy bodies (DLB, N=1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.
2022-02-20 | MSV000088875 | MassIVE