Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Parkinson’s disease associated LRRK2-G2019S variant restricts serine metabolism leading to microglia inflammation and dopaminergic neuron degeneration

ABSTRACT: A mounting body of evidence reveals that inflammation is a major hallmark in the pathophysiology of Parkinson’s disease (PD). Notably, microglia are key players in orchestrating neuroinflammatory signalling pathways in the brain. However, the molecular mechanisms underlying the microglial response in the dopaminergic neuron degeneration remain unclear. In this study, we investigated the role of the PD-associated LRRK2-G2019S variant in microglial neurotoxicity that potentially drives the loss of dopaminergic neurons. Using PD patient-specific induced pluripotent stem cell-based models, we showed that microglia harbouring the LRRK2-G2019S mutation exhibited increased activation markers, phagocytic capacity, and secretion of inflammatory cytokines such as TNF-α. This was linked to metabolic dysregulation, including higher levels of glycolysis and a reduction in serine biosynthesis. These overactivated microglia drove dopaminergic neuron degeneration in a 3D midbrain organoid model. Intriguingly, addressing the PD associated metabolic disturbances reduced the inflammatory state of the microglia and reversed neuronal loss. These findings reinforce the immunometabolic control of microglia to preserve dopaminergic neuron integrity and its pivotal role in PD pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282494 | GEO | 2025/10/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson’s disease

Project description:Astrocytes are essential cells of the central nervous system, characterized by dynamic relationships with neurons that range from functional metabolic interactions and regulation of neuronal firing activities, to the release of neurotrophic and neuroprotective factors. In Parkinson’s disease (PD), dopaminergic neurons are a vulnerable population progressively lost during the course of the disease, but the effects of PD on astrocytes and astrocyte-to-neuron communication remains mostly unknown. This study focuses on the effects of the PD-related mutation LRRK2 G2019S in astrocytes, using patient-derived induced pluripotent stem cells. We report the alteration of extracellular vesicle (EV) biogenesis in astrocytes, and we identify the abnormal accumulation of key PD-related proteins within multi vesicular bodies (MVBs). We found that dopaminergic neurons internalize astrocyte-secreted EVs but LRRK2 G2019S EVs are abnormally enriched in the neurites and provide only marginal neurotrophic support to dopaminergic neurons. Thus, dysfunctional astrocyte-to-neuron communication via altered EV biological properties could participate in the progression of PD.

2021-10-06 | GSE152768 | GEO

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

Ribosome profiling of G2019S LRRK2 human dopamine neurons

Project description:G2019S mutaion of LRRK2 is known to increase mRNA translation. We perform ribosome profiling to study defective translation using human dopamine neuron models. Patient-derived human dopamine neurons with G2019S LRRK2 mutation were generated and used. Also a mutation-corrected isogenic pair line was used.

2018-07-01 | GSE90469 | 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

The Parkinson’s disease associated LRRK2-G2019S variant restricts serine metabolism leading to microglia inflammation and dopaminergic neuron degeneration

Project description:The Parkinson’s disease associated LRRK2-G2019S variant restricts serine metabolism leading to microglia inflammation and dopaminergic neuron degeneration

| PRJNA1189015 | ENA

Gene expression data from LRRK2-WT and LRRK2-G2019S astrocytes

Project description:LRRK2-G2019S (LRRK2-GS), a pathogenic mutation in the PD-associated gene LRRK2, promote ER stress-induced cell death by reducing transcriptional activity of X-box-binding protein 1 (XBP1), a key transcription factor of the UPR. We used microarrays to detail the programme of gene expression and identified distinct classes of up-regulated or down-regulated genes during ER stress.

2019-10-31 | GSE139579 | GEO

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

Project description: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.

2025-06-27 | GSE284454 | GEO

Modelling G2019S-LRRK2 sporadic Parkinson’s disease in 3D midbrain organoids

Project description:Recent advances in generating 3 dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson’s disease-associated LRRK2 G2019S mutation. LRRK2-G2019S midbrain organoids derived from LRRK2 targeted human iPSCs in vitro have LRRK2-associated sporadic Parkinson's disease phenotypes. Midbrain-like 3D organoids expressing LRRK2-G2019S showed dynamic changes in globle gene expression.

2019-02-02 | GSE125234 | 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

Differential serum microRNAs in premotor LRRK2 G2019S carriers from Parkinson’s disease

Project description:The LRRK2 G2019S pathogenic mutation causes LRRK2-associated Parkinson’s disease (L2PD) with incomplete penetrance. LRRK2 non-manifesting carriers (L2NMC) are at PD high risk but predicting pheno-conversion is challenging given the lack of progression biomarkers. To investigate novel biomarkers for PD premotor stages, we performed a longitudinal microRNA (miRNA) assessment of serum samples from G2019S L2NMC followed-up over 8 years. Our cohort consisted of G2019S L2NMC stratified by dopamine transporter single-photon emission computed tomography (DaT-SPECT) into DaT-negative (n=20) and DaT-positive L2NMC (n=20), pheno-converted G2019S L2PD patients (n=20), idiopathic PD (iPD) (n=19), and controls (n=40). We also screened a second cohort of L2PD patients (n=19) and controls (n=20) (Total n=158). Compared to healthy controls, we identified 8 deregulated miRNAs in DaT-negative L2NMC, 6 in DaT-positive L2NMC, and one in L2PD. Between groups, the highest miRNA differences, 24 candidate miRNAs, occurred between DaT-positive L2NMC and L2PD. Longitudinally, we found 11 common miRNAs with sustained variation in DaT-negative and DaT-positive L2NMCs compared to their baselines. Our study identifies novel miRNA alterations in premotor stages of PD co-occurring with progressive DaT-SPECT decline before motor manifestation, whose deregulation seems to attenuate after the diagnosis of L2PD. Moreover, we identified 4 miRNAs with relatively high discriminative ability (AUC=0.82) between non-pheno-converted DaT-positive G2019S carriers and pheno-converted L2PD patients (miR-4505, miR-8069, miR-6125, and miR-451a), which hold potential as early progression biomarkers for PD.

2023-01-06 | GSE221543 | GEO

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