Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Gut commensal Parabacteroides goldsteinii mitigates LRRK2 Parkinsonism by reducing neuroinflammation and enhancing gut homeostasis

ABSTRACT: Evidence suggests that Lewy body pathology in Parkinson's disease (PD) may originate in the gut, with intestinal inflammation serving as an early mediator via the gut-brain axis. Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common genetic risk factor for both PD and inflammatory bowel disease. We proposed that modulating the gut microenvironment could assist in mitigating PD progression, particularly in individuals with LRRK2 mutations. Our study indicates that germ-free condition could only partially alleviate PD process in LRRK2 G2019S mice. Mono-inoculation of PG in germ-free LRRK2 G2019S mice mitigated age-dependent motor dysfunction. In the brain, the colonic P. goldsteinii treatment reduces neuronal a-synuclein expression, ease neuroinflammation, and mitigates dopaminergic degeneration. In the gut, the PG administration suppressed the toll-like receptor 4 signaling, facilitated the differentiation of intestinal dendritic cells and macrophages, and increased the abundance of anti-inflammatory T cells. Our findings demonstrated that colonization by P. goldsteinii alleviates the progression of PD by exerting multifaceted effects in maintaining intestinal homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE284454 | GEO | 2025/06/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Genome-wide expression profiling of the LRRK2-G2019S mutation in hNES cells

Project description:Parkinson’s disease (PD) has a neuro-developmental component with multiple genetic predispositions. The most prevalent mutation, LRRK2-G2019S is linked to familial and sporadic PD. Based on the multiple origins of PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patient genetic background act as susceptibility factors for developing PD. To assess the developmental component of LRRK2-G2019S pathogenesis, we used 19 human iPSC-derived neuroepithelial stem cell lines (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal. Within patients, phenotypes were only partly LRRK2-G2019S dependent, suggesting Parkinson’s disease (PD) has a neuro-developmental component with multiple genetic predispositions. The most prevalent mutation, LRRK2-G2019S is linked to familial and sporadic PD. Based on the multiple origins of PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patient genetic background act as susceptibility factors for developing PD. To assess the developmental component of LRRK2-G2019S pathogenesis, we used 19 human iPSC-derived neuroepithelial stem cell lines (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal. Within patients, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. We identified Serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the abberant phenotypes. Its enzymatic product, D-Serine, rescued altered NESC renewal. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment.

2018-03-07 | GSE101534 | GEO

Neural stem cells of Parkinson’s disease patients exhibit aberrant mitochondrial morphology and functionality

Project description:Emerging evidence suggest that Parkinson's disease (PD), besides being an age-associated disorder, might also have a neurodevelopment component. Disruption of mitochondrial homeostasis has been highlighted as a crucial cofactor in its etiology. Here, we show that PD patient-specific human neuroepithelial stem cells (NESCs) carrying the LRRK2-G2019S mutation recapitulate key mitochondrial defects previously described only in differentiated dopaminergic neurons. By combining high-content imaging approaches, 3D image analysis, and functional mitochondrial readouts we show that LRRK2-G2019S mutation caused aberrations in mitochondrial morphology and functionality compared to isogenic controls. LRRK2-G2019S NESCs displayed an increased number of mitochondria compared to isogenic control lines. However, these mitochondria were more fragmented and exhibited decreased membrane potential. Coherently, the release of total and mitochondrial redox oxidative species increased in LRRK2-G2019S NESC compared to controls. Functional alterations in LRRK2-G2019S cultures were also accompanied by a reduced mitophagic clearance via lysosomes. These findings support the hypothesis that preceding mitochondrial developmental defects contribute to the manifestation of the PD pathology later in life.

2019-03-09 | GSE128040 | GEO

LRRK2 G2019S mutation incites increased cell-intrinsic neutrophil effector functions and intestinal inflammation in a model of infectious colitis.

Project description:Parkinson’s Disease (PD) is a progressive, neurodegenerative disorder characterised by motor and non-motor symptoms. People with PD often present with gastrointestinal dysfunction, such as constipation, and studies have indicated that PD is more common in people with inflammatory bowel disease (IBD). Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are responsible for approximately 1% of all PD cases and increased risk for inflammatory bowel disease (IBD). Among them, the LRRK2 Gly2019Ser is the most common PD-associated mutation. It is unknown how LRRK2 mutation affects intestinal inflammation susceptibility or pathogenesis of PD. Here we demonstrate that LRRK2 G2019S mutation promotes increased neutrophils migration and differential gene regulation and cell function in these cells in Citrobacter rodentium-infected mice. We found a cell-intrinsic function for LRRK2 G2019S in vivo, in increasing neutrophil chemotaxis, degranulation and NETosis, and an upregulation of Th17 immune responses, which may together contribute to the observed increased colon pathology. Transcriptionally, these neutrophils have a greater pro-inflammatory type I and II IFN response compared to WT mice. Our results increase our understanding of the role of PD-associated genes in immune cells and their contribution to immune dysregulation, which could contribute to the development of pharmacological targets and biomarkers for an easier detection and intervention in PD.

2024-11-29 | GSE283183 | GEO

Expression mRNA data from mouse blood samples measured using the NanoString nCounter platform

Project description:Background: The diagnosis of Parkinson’s disease (PD) is usually not established until advanced neurodegeneration leads to clinically detectable symptoms. Previous blood PD transcriptome studies show low concordance, possibly due to the use of microarray technology, which has high measurement variation. The Leucine-rich repeat kinase 2 (LRRK2) G2019S mutation predisposes to PD. Using preclinical and clinical studies, we sought to develop a novel statistically motivated transcriptomic-based approach to identify a molecular signature in the blood of Ashkenazi Jewish PD patients including LRRK2 mutation carriers. Methods: Using a digital gene expression platform to quantify 175 mRNA markers with low coefficients of variation (CV), we first compared whole blood transcript levels in mouse models 1) over-expressing wild-type (WT) LRRK2, 2) overexpressing G2019S LRRK2, 3) lacking LRRK2 (knockout), 4) and in WT controls. We then studied an Ashkenazi Jewish cohort of 34 symptomatic PD patients (both WT LRRK2 and G2019S LRRK2) and 32 asymptomatic controls. Results: The expression profiles distinguished the 4 mouse groups with different genetic background. In patients, we detected significant differences in blood transcript levels both between individuals differing in LRRK2 genotype and between PD patients and controls. Discriminatory PD markers included genes associated with innate and adaptive immunity and inflammatory disease. Notably, gene expression patterns in L-DOPA-treated PD patients were significantly closer to those of healthy controls in a dose-dependent manner. Conclusions: We identify whole blood low CV mRNA signatures correlating with LRRK2 genotype and with PD disease state. This approach may provide insight into pathogenesis and a route to early disease detection.

2015-10-17 | GSE62470 | GEO

Expression mRNA data from human blood samples measured using the NanoString nCounter platform

2015-10-17 | GSE62469 | GEO

RNA-Seq of LRRK2 G2019S Parkinson’s iPSC-derived astrocytes

Project description:Non-neuronal cell types such as astrocytes can contribute to Parkinson’s disease (PD) pathology. The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is one of the most common known causes of familial PD. To characterize its effect on astrocytes, we developed a protocol to produce midbrain-patterned astrocytes from human induced pluripotent stem cells (iPSCs) derived from PD LRRK2 G2019S patients and healthy controls. In order to understand the effect of this mutation on astrocyte function, we compared the gene expression profiles of iPSC-derived midbrain-patterned astrocytes from PD patients with those from healthy controls.

2018-09-22 | GSE120306 | GEO

Ribosome profiling experiments of LRRK2 mouse models

Project description:G2019S mutaion of LRRK2 is known to increase mRNA translation. We perform ribosome profiling to study defective translation in mammalian LRRK2 models. We used G2019S LRRK2 transgenic mice, G2019S/D1994A LRRK2 transgenic mice, LRRK2 knockout mice.

2021-02-27 | GSE167704 | GEO

Mutations in LRRK2 linked to Parkinson’s disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson’s disease (PD) while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in over-expression cell models while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in post-mortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild type mice, accompanied by striatal accumulation of ferritin. Conclusion: Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia. Neuroinflammation remodels endolysosomal gene expression in microglia, in vitro and in vivo.

2021-10-29 | GSE186559 | GEO

Gene expression analysis of human iPSC generated from pathogenic LRRK2 (G2019S) mutation bearing patients

Project description:Genetic mutations on leucine-rich repeat kinase 2 (LRRK2) have been associated with an increased risk of Parkinson's disease. The Gly2019Ser (G2019S) mutation on LRRK2 gene is a relatively common cause of familial Parkinson's disease in Caucasian population. In this study, we generated human induced pluripotent stem cell (iPSC) lines from LRRK2 (G2019S) bearing patient fibroblasts by cell reprogramming. We performed global gene expression profiling of LRRK2 (G2019S) heterozygous and homozygous patient iPSC lines, and the corresponding fibroblast lines they originated from. An age-matched wildtype human fibroblast line and H1 human embryonic stem cell (ESC) line were used as controls. Microarray gene expression profiling was done to: (1) Compare global gene expression differences between wildtype fibroblasts and fibroblasts from patients bearing homozygous and heterozygous LRRK2 (G2019S) mutation; (2) Compare global gene expression differences between wildtype iPSC and iPSC generated from LRRK2 (G2019S) homozygous and heterozygous patients; (3) Check that all iPSC generated from wildtype and patients fibroblasts are in fact similar to human pluripotent ESC.

2012-10-17 | E-GEOD-33298 | biostudies-arrayexpress

Phospho-proteome analysis of PBMCs in LRRK2 mutation carriers: expansion & validation of findings of the Barcelona LRRK2 Biorepository

Project description:Supported by the Michael J Fox Foundation we established a biorepository of blood cells from G2019S LRRK2-PD patients recruited at the Hospital Clínic de Barcelona (Barcelona). Using this cohort, we performed a phospho-proteomic pilot study by mass spectrometry and identified a differential combination of phosphorylated proteins associated with the G2019S mutation. Here, we aim to validate and expand these findings using additional G2019S and R1441G cohorts (PMID: 35049090 By state-of-the-art DIA phospho-proteomics we aim to validate and expand our preliminary findings in additional G2019S and R1441G LRRK2 cohorts of similar design, size, and blood cell collection methods collected at additional centers in Spain (Hospital de Valdecilla in Santander, Hospital de Donostia in San Sebastian). We expect to identify differential protein phosphorylation changes in LRRK2-PD patients affected by the G2019S and R1441G mutations that could be useful as LRRK2 pharmacodynamic biomarkers. In asymptomatic LRRK2 mutation carriers, we will explore the presence of these phosphorylation changes and evaluate their applicability as early disease biomarkers.

2025-06-09 | PXD050865 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data