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Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson’s disease and Dementia with Lewy bodies

ABSTRACT: Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson’s disease and Dementia with Lewy bodies

PROVIDER: PRJNA1192295 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31555320.fastq.gz	Fastqsanger.gz
	SRR31555321.fastq.gz	Fastqsanger.gz
	SRR31555322.fastq.gz	Fastqsanger.gz
	SRR31555323.fastq.gz	Fastqsanger.gz
	SRR31555324.fastq.gz	Fastqsanger.gz

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Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson’s disease and Dementia with Lewy bodies

Project description:GBA mutations are major risk factors for Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB), two common α-synucleinopathies associated with cognitive impairment. Here, we investigated the role of GBA mutations in cognitive decline by utilizing Gba L444P mutant mice, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice showed early cognitive deficits but no PD-like motor deficits up to 12 months old. Conversely, SNCA tg mice displayed age-related motor deficits but no cognitive abnormalities. Gba-SNCA mice exhibited exacerbated motor deficits and cognitive decline. Immunohistological analysis revealed cortical phospho-α-synuclein pathology in SNCA tg mice, which was exacerbated in Gba-SNCA mice, especially in layer 5 cortical neurons. Significantly, Gba mutant mice did not show α-synuclein pathology. Single-nucleus RNA sequencing of cortices instead uncovered selective synaptic vesicle cycle defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via robust downregulation in gene networks regulating synapse vesicle cycle and synapse assembly. Meanwhile SNCA tg mice displayed broader synaptic changes. Immunohistochemical and electron microscopic analyses validated these findings. Together, our results indicate that Gba mutations, while exacerbating pre-existing α-synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through α-synuclein-independent mechanisms, likely involving dysfunction in synaptic vesicle endocytosis. Additionally, Gba-SNCA mice are a valuable model for studying cognitive and motor deficits in PD and DLB

2025-04-15 | GSE283187 | GEO

Olfactory proteomics in Dementia with Lewy bodies

Project description:Proteomic analysis were performed in olfactory bulbs derived from controls and individuals with dementia with lewy bodies

2021-09-08 | PXD016069 | Pride

Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson's disease and Dementia with Lewy bodies.

Project description: Not available

| S-EPMC11527026 | biostudies-literature

Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson's disease and Dementia with Lewy bodies.

Project description: Not available

| S-EPMC11703330 | biostudies-literature

Methylation profiling by array for Dementia with Lewy Bodies using brain tissue

Project description:Synucleinopathies encompass Parkinsons disease (PD), dementia with Lewy bodies (DLB), and Parkinsons disease dementia (PDD) and are recognized for presenting a range of cognitive, neuropsychiatric, sleep-related, motor, and autonomic symptoms. DLB manifests with early-onset dementia when Lewy bodies develop in the brainstem and cerebral cortex. We profiled the DNA methylation using the post-mortem brain tissue from the parietal cortex, specifically Brodmann area 7 and compared them with age-, and sex-matched controls. Through the integration of multi-omics approaches, we anticipate the identification of notable alterations in these well-defined samples. Additionally, our objective is to study the biochemical perturbations in the brain tissue of those individuals who died with DLB. Differentially Methylated Cytosines (DMCs) and metabolites were identified, followed by pathway enrichment analysis. Correlations between methylation changes and metabolite levels were explored. Methylation profiling revealed 3,478 significant DMCs, predominantly hypermethylated, enriched in CpG islands and gene regions related to transcription start sites. Pathway analysis identified 612 significant pathways, with notable involvement in olfactory and synaptic functions. Metabolomics profiling identified 15 significantly differentially abundant metabolites. The top perturbed pathway was Phosphatidylethanolamine (PE) Biosynthesis. Further, key correlations were found between significant DMCs and metabolites, particularly in the Phosphatidylethanolamine Biosynthesis pathway involving genes PTDSS1 and PCYT2. Further, ignsificant sex-specific epigenetic and metabolomic changes were also observed. This comprehensive analysis of DNA methylation and metabolomics in DLB highlights significant biomarkers and pathways, offering insights into disease mechanisms and potential therapeutic targets.

2025-01-15 | GSE272947 | GEO

A Study of Small RNAs from Cerebral Neocortex of Pathology-Verified Alzheimer’s Disease, Dementia with Lewy Bodies, Hippocampal Sclerosis, Frontotemporal Lobar Dementia, and Non-Demented Human Controls

Project description:MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes. All cases had short postmortem intervals, relatively high-quality RNA, and state-of-the-art neuropathological diagnoses. The resulting data (over 113 million reads in total, averaging 5.6 million reads per sample) and secondary expression analyses constitute an unprecedented look into the human cerebral cortical miRNome at single nucleotide resolution. While we find no apparent changes in isomiR or miRNA editing patterns in correlation with ND pathology, our results validate and extend previous miRNA profiling studies with regard to quantitative changes in NDs. In agreement with this idea, we provide independent cohort validation for changes in miR-132 expression levels in AD (n = 8) and FTLD (n = 14) cases when compared to controls (n = 8). The identification of common and ND-specific putative novel brain miRNAs and/or short-hairpin molecules is also presented. The challenge now is to better understand the impact of these and other alterations on neuronal gene expression networks and neuropathologies. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes.

2013-04-18 | E-GEOD-46131 | biostudies-arrayexpress

Synaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson's disease and dementia with Lewy bodies.

Project description: Not available

| S-EPMC12475166 | biostudies-literature

Altered ceramide metabolism is a feature in the extracellular vesicle mediated spread of alpha-synuclein in sporadic and GBA-linked Lewy body disease

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

Lewy body dementia promotion by air pollutants

Project description:Lewy body dementia promotion by air pollutants

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Dementia with Lewy bodies post-mortem brains reveal differentially methylated CpG sites with biomarker potential

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.

2022-09-08 | GSE190348 | GEO

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