Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effect of mutation of LRRK2-P1446L on gene expression in substantia nigra of 16 months C57BL/6 mice

ABSTRACT: Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, with growing evidence implicating leucine-rich repeat kinase 2 (LRRK2) and neuroinflammation in its pathogenesis. In this study, we investigated the novel LRRK2 P1446L mutation and demonstrated its pivotal role in driving dopaminergic neurodegeneration through the dysregulation of death-associated protein kinase 1 (DAPK1)-mediated neuronal survival pathways. We found that this mutation induces DAPK1 overexpression, which concurrently activates mitochondrial apoptosis and exacerbates neuroinflammation via PI3K-Akt-dependent NF-κB activation. Notably, we identified a previously unrecognized DAPK1-Tuftsin regulatory axis, wherein DAPK1 upregulation suppresses the neuroprotective peptide Tuftsin, thereby aggravating neuronal vulnerability. Our findings establish DAPK1 as a central node linking LRRK2 P1446L to multiple PD-related pathological processes, and propose combined targeting of DAPK1 activity and Tuftsin restoration as a promising therapeutic strategy for LRRK2-associated Parkinson's disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE307275 | GEO | 2026/09/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

LRRK2-mediated neuroinflammation induced neuronal dysfunctions in a Parkinson’s and Alzheimer’s disease cellular model

Project description:Dissect the transcriptional consequences of neuroinflammation and the role of the kinase LRRK2 in regulating neuronal responses in human induced pluripotent stem cell (hiPSC)-derived neurons exposed to pro-inflammatory conditions relevant to Parkinson’s disease (PD) and Alzheimer’s disease (AD).Dopaminergic neurons (PD context) and cholinergic neurons (AD context) were differentiated from hiPSCs and subsequently cultured in glial-conditioned medium containing either α-synuclein pre-formed fibrils (α-syn pffs) or amyloid-β (Aβ) fibrils, for PD and aAD respectively. Neuronal cultures were exposed to inflammed media to model chronic inflammatory stress.

2025-10-02 | GSE308143 | GEO

Gene expression analysis of H9 hESC derived neuron stem cells (NSC) harboring pathogenic LRRK2 (G2019S) mutation

2012-10-17 | E-GEOD-36321 | biostudies-arrayexpress

Gene and microRNA transcriptome analysis of Parkinson's related LRRK2 mouse models

Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial and sporadic ParkinsonM-bM-^@M-^Ys disease (PD). Here, we investigated in parallel gene and microRNA transcriptome profiles of three different LRRK2 mouse models. Striatal tissue was isolated from adult LRRK2 knockout mice, as well as mice expressinghuman LRRK2 wildtype (hLRRK2-WT) or PD-associated R1441G mutation (hLRRK2-R1441G). We used microarraya to measure gene and microRNA expression levels in various LRRK2 mouse models. LRRK2 wildtype and knockout mice were bred on a C57BL/6 background. LRRK2 non-transgenic and hLRRK2 transgenic mice were bred on a FVB/N background.

2013-11-22 | E-GEOD-52584 | biostudies-arrayexpress

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 H9 hESC derived neuron stem cells (NSC) harboring pathogenic LRRK2 (G2019S) mutation

2012-10-17 | GSE36321 | GEO

The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner

Project description:Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered. We demonstrate here that the R1441C mutation induces a hyper-responsive phenotype in macrophages from young female mice, characterized by increased effector functions, including stimulation-dependent antigen presentation, cytokine release, phagocytosis, and lysosomal function. This is followed by age-acquired immune cell exhaustion in a Lrrk2-kinase-dependent manner. Immune-exhausted macrophages exhibit suppressed antigen presentation and hypophagocytosis, which is also demonstrated in myeloid cells from R1441C and Y1699C-PD patients. Our novel findings that LRRK2 mutations confer immunological advantage at a young age but may predispose the carrier to age-acquired immune exhaustion have significant implications for LRRK2 biology and therapeutic development. Indeed, LRRK2 has become an appealing target in PD, but our findings suggest that more research is required to understand the cell-type specific consequences and optimal timing of LRRK2-targeting therapeutics.

2024-01-31 | GSE246691 | GEO

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

Project description: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.

2025-10-31 | GSE282494 | 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

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

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