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Cross talks between mutant Leucine Rich Repeat Kinase 2 in the peripheral immune system and the CNS regulate neurodegeneration after environmental insult - part 2

ABSTRACT: Missense mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene result in late-onset Parkinson’s disease (PD). The incomplete penetrance of LRRK2 mutations in humans and LRRK2 murine models of PD suggests that the disease may result from a complex interplay of genetic predispositions and persistent exogenous insults. To examine molecular pathways that might be affected by mutant LRRK2 in peripheral leukocytes, we performed mass spectrometry analysis (tandem mass tagging, TMT) on peripheral blood mononuclear cells obtained from intact and acute LPS-challenged WT and R1441G mutant mice.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Peripheral Blood Mononuclear Cell

DISEASE(S): Parkinson's Disease

SUBMITTER: Timothy Shaw

LAB HEAD: Junmin Peng

PROVIDER: PXD006289 | Pride | 2018-05-03

REPOSITORIES: Pride

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			Action	DRS
	PbmcTf10.1.pepXML	Pepxml
	PbmcTf10.raw	Raw
	PbmcTf12.1.pepXML	Pepxml
	PbmcTf12.raw	Raw
	PbmcTf14.1.pepXML	Pepxml

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Cross talks between mutant Leucine Rich Repeat Kinase 2 in the peripheral immune system and the CNS regulate neurodegeneration after environmental insult - part 1

Project description:Missense mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene result in late-onset Parkinson’s disease (PD). The incomplete penetrance of LRRK2 mutations in humans and LRRK2 murine models of PD suggests that the disease may result from a complex interplay of genetic predispositions and persistent exogenous insults. To achieve a detailed characterization of the altered neuroinflammatory reaction in the brain of mutant LRRK2 mice, we performed mass spectrometry analysis (tandem mass tagging, TMT) of brain tissue obtained from intact and acute LPS-challenged WT and R1441G mutant mice.

2018-05-03 | PXD006290 | Pride

R1441G but not G201S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils

Project description:Gain-of kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause Parkinson’s disease (PD), albeit with incomplete and age-dependent penetrance, offering the prospect of disease-modifying treatment strategies via LRRK2 kinase inhibition. LRRK2 phosphorylates a subgroup of RabGTPases including Rab10 and pathogenic mutations enhance LRRK2-mediated phosphorylation of Rab10 at Thr73. In this study we analyse LRRK2 dependent Rab10Thr73 phosphorylation in human peripheral blood neutrophils isolated from 101 individuals using quantitative immunoblotting and mass spectrometry. Our cohort includes 42 LRRK2 mutation carriers (21 with the G2019S mutation that resides in the kinase domain and 21 with the R1441G mutation that lies within the ROC-COR domain), 27 patients with idiopathic PD, and 32 controls. We show that LRRK2 dependent Rab10 Thr73 phosphorylation is significantly elevated in all R1441G LRRKR2 mutation carriers irrespective of disease status. PD manifesting and non-manifesting G2019S mutation carriers as well as idiopathic PD samples did not display elevated Rab10 Thr73 phosphorylation. Furthermore, we analysed brain samples of 10 G2019S and 1 R1441H mutation carriers as well as 10 individuals with idiopathic PD and 10 controls. We find high variability for pRab10Thr73 phosphorylation amongst donors irrespective of genetic and disease state. We conclude that in vivo LRRK2 dependent pRab10Thr73 analysis in human peripheral blood neutrophils is a specific and robust biomarker for LRRK2 kinase activation for individuals with mutations such as R1441G that enhance pRab10Thr73 phosphorylation over 2-fold. We provide the first evidence that the LRRK2 R1441G mutation enhances LRRK2 kinase activity in a primary human cell.

2021-09-10 | PXD024898 | Pride

Single cell RNA sequencing reveals limited effects of Lrrk2 genotype in a mouse model of acute CNS inflammation

Project description:BACKGROUND: Previous data implicates neuroinflammation in the pathogenesis of Parkinson’s disease (PD). Of the genes associated with PD, Leucine rich repeat kinase 2 (LRRK2) is expressed in microglia, resident brain inflammatory cells. However, the extent to which LRRK2 affects neuroinflammatory responses is unclear. OBJECTIVE: To examine whether mutations in Lrrk2 affect responses to neuroinflammation in vivo. METHODS: We injected cohorts of mice carrying mutations in Lrrk2, homologous to those causing human PD, with a single intrastriatal injection of lipopolysaccharide (LPS) or control. We used single cell RNA-Sequencing to examine cell type specific responses to treatment and genotype and validated key results with orthogonal approaches. RESULTS: We found that our chosen paradigm of acute LPS exposure evokes robust transcriptional changes consistent with a multicellular neuroinflammatory response. We also found evidence of peripheral immune cell recruitment into the brain and interaction with brain-resident microglia. However, the transcriptional effects of Lrrk2 mutations were limited to small numbers of genes, including down regulation of gene ontogeny terms related to lysosomes, predominantly in microglia. CONCLUSIONS: Our data clearly demonstrate that many cells in the brain respond to a single inflammatory insult with strong transcriptional responses and that, even in a model focussed on CNS injection, there is interaction between peripheral and central immune cells. In contrast, the quantitative effects of Lrrk2 mutations are modest at least at the level of transcription, demonstrating that additional studies are needed to clarify whether Lrrk2 affects neuroinflammation in an endogenous context.

2024-04-29 | GSE265833 | 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

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

Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice

Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) segregate with familial Parkinson’s disease (PD) and genetic variation in LRRK2 contributes to risk of sporadic disease. Although knockout of LRRK2 or knock-in of pathogenic mutations into the mouse germline does not result in a PD phenotype, several defects have been reported in the kidneys of LRRK2 knockout mice. To understand LRRK2 function in vivo, we used an unbiased approach to determine which protein pathways are affected in LRRK2 knockout kidneys. We performed two iTRAQ screens on cytosol- and microsome-enriched fractions from 12-month old LRRK2-KO and G2019S knockin kidneys compared to wild type controls. We nominated changes in cytoskeletal-associated proteins, lysosomal proteases, proteins involved in vesicular trafficking and in control of protein translation in LRRK2-KO. Changes were not seen in mice expressing the pathogenic G2019S LRRK2 mutant.

2022-03-01 | PXD008531 | Pride

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.

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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 Parkinson’s 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).

2013-11-22 | GSE52584 | 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

Microarray expression analysis in idiopathic and LRRK2-associated Parkinson's disease

Project description:LRRK2 mutations are the most common genetic cause of Parkinson’s disease (PD). We performed a whole-genome RNA profiling of putamen tissue from idiopathic PD (IPD), LRRK2-associated PD (G2019S mutation), neurologically healthy controls and one asymptomatic LRRK2 mutation carrier, by using the Genechip Human Exon 1.0-ST Array. The differentially expressed genes found in IPD revealed an alteration of biological pathways related to long term potentiation (LTP), GABA receptor signalling, and calcium signalling pathways, among others. These pathways are mainly related with cell signalling cascades and synaptic plasticity processes. They were also altered in the asymptomatic LRRK2 mutation carrier but not in the LRRK2-associated PD group. The expression changes seen in IPD might be attributed to an adaptive consequence of a dysfunction in the dopamine transmission. The lack of these altered molecular pathways in LRRK2-associated PD patients suggests that these cases could show a different molecular response to dopamine transmission impairment.

2011-11-10 | GSE23290 | GEO

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