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LRRK2 signalling pathway in Mycobacterium tuberculosis

ABSTRACT: LRRK2 promotes Mycobacterium tuberculosis clearance by regulating phagosome maturation in mouse macrophages

INSTRUMENT(S): LTQ Orbitrap, Q Exactive

ORGANISM(S): Mycobacterium Tuberculosis Mus Musculus (mouse)

TISSUE(S): Macrophage

DISEASE(S): Parkinson's Disease

SUBMITTER: julien peltier

LAB HEAD: Matthias Trost

PROVIDER: PXD006909 | Pride | 2018-05-16

REPOSITORIES: Pride

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	150816_ash_jp_raw_latexB_pp_Ctrl_01.raw.gz	Raw
	150816_ash_jp_raw_latexB_pp_Ctrl_02.raw.gz	Raw
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Publications

LRRK2 is a negative regulator of <i>Mycobacterium tuberculosis</i> phagosome maturation in macrophages.

Härtlova Anetta A Herbst Susanne S Peltier Julien J Rodgers Angela A Bilkei-Gorzo Orsolya O Fearns Antony A Dill Brian D BD Lee Heyne H Flynn Rowan R Cowley Sally A SA Davies Paul P Lewis Patrick A PA Ganley Ian G IG Martinez Jennifer J Alessi Dario R DR Reith Alastair D AD Trost Matthias M Gutierrez Maximiliano G MG

The EMBO journal 20180522 12

Mutations in the leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, chronic inflammation and mycobacterial infections. Although there is evidence supporting the idea that LRRK2 has an immune function, the cellular function of this kinase is still largely unknown. By using genetic, pharmacological and proteomics approaches, we show that LRRK2 kinase activity negatively regulates phagosome maturation via the recruitment of the Class III phosphatidylinositol-3 kinase comp ...[more]

PMID: 29789389

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

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

PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins

Project description:Mutations that activate LRRK2 protein kinase cause Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with effectors. An siRNA screen of all protein phosphatases revealed that a poorly studied protein phosphatase, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab proteins. PPM1H knock out increased endogenous Rab phosphorylation and inhibited Rab dephosphorylation. Overexpression of PPM1H suppressed LRRK2-mediated Rab phosphorylation. PPM1H also efficiently and directly dephosphorylated Rab8A in biochemical studies. A “substrate-trapping” PPM1H mutant (Asp288Ala) binds with high affinity to endogenous, LRRK2-phosphorylated Rab proteins, thereby blocking dephosphorylation seen upon addition of LRRK2 inhibitors. PPM1H is localized to the Golgi and its knockdown suppresses primary cilia formation, similar to pathogenic LRRK2. Thus, PPM1H acts as a key modulator of LRRK2 signaling by controlling dephosphorylation of Rab proteins. PPM1H activity enhancers could offer a new therapeutic approach to prevent or treat Parkinson’s disease

2019-11-06 | PXD014794 | Pride

Pacific oyster phagosome LC-MSMS

Project description:Phagosomes are task-force organelles of innate immune systems responsible for the recognition, processing, and ultimately destruction of invading microorganisms. Among invertebrate and vertebrate species, evolutionary diversity and continuity abound in the protein machinery executing this coordinately regulated process, though its dynamics and full scope of regulators remain incompletely understood. In order to clarify molecular mechanisms underlying phagocytosis, we studied phagocyte response to beads and Vibrio species, using hemocytes of the Pacific oysters (Crassostrea gigas) as a marine invertebrate model. Phagosomes from different stages of phagocytosis were isolated by density-gradient centrifugation, and more than 400 phagosome-associated proteins were subsequently identified via high-throughput quantitative proteomics. In modeling key networks of phagosomal protein-protein interactions, our results support the essential roles of several processes driving phagosome formation and maturation, including actin cytoskeleton remodeling, and signal transduction by myosin and Rab proteins. In further quantitative proteomic analysis, trends of both upregulation and downregulation of protein expression were observed proteins during phagosome formation and maturation. Notably, the signal transducers CgRhoGDI and CgPI4K were implicated. In addition, six Rab proteins including Rab1, Rab2, Rab7, Rab11, RaB21, and Rab33 were also identified as active regulators or mediators in hemocyte phagocytosis. Our current work illustrates the diversity and dynamic interplay of phagosomal proteins, providing a framework for better understanding host-microbe interactions during phagosome formation and maturation in under-examined invertebrate species.

2020-04-27 | PXD015810 | Pride

Transcription profiling by array of mouse embryonic stem cells from wildtype and LRRK2-deficient mice to investigate the effects of LRRK2 on neuronal differentiation

Project description:Wildtype and LRRK2-deficient mouse embryonic stem (ES) cells were used to investigate the effects of LRRK2 on neuronal differentiation.

2011-10-27 | E-MEXP-2963 | biostudies-arrayexpress

Examination of impact of pathogenic mutations in LRRK2 upon gene expression in patient fibroblasts and HEK cells

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

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2022-03-01 | PXD008531 | Pride

Development of a multiplex targeted mass spectrometry assay to quantify levels of LRRK2 phosphorylated Rab substrates and Ser910 and Ser935 biomarker sites

Project description:Mutations that increase the protein kinase activity of LRRK2 are one of the most common causes of familial Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif, impacting interaction with effectors. We describe and validate a new, multiplex targeted mass spectrometry assay to quantify endogenous levels of LRRK2 phosphorylated Rab substrates (Rab1, Rab3, Rab8, Rab10, Rab35 and Rab43) as well as total levels of Rabs, LRRK2 and phosphorylation of the LRRK2 Ser910 and Ser935 biomarker sites. Exploiting this assay, we quantify for the first time the relative levels of each of the pRab proteins in different cells (mouse embryonic fibroblasts & human neutrophils) and mouse tissues (brain, lung, kidney and spleen). We define how each of the different pRab proteins are impacted by Parkinson’s pathogenic LRRK2[R1441C] and VPS35[D620N] mutations as well as LRRK2 inhibitors. We find that the VPS35[D620N], but not LRRK2[R1441C] mutation, enhances Rab1 phosphorylation in a manner blocked by administration of an LRRK2 inhibitor, providing the first evidence that LRRK2 can phosphorylate Rab1 physiologically. We argue that this targeted mass spectrometry assay can replace immunoblotting approaches currently deployed to assess LRRK2 Rab signalling pathway.

2021-03-17 | PXD022662 | Pride

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

Mapping of nanobody binding sites on human LRRK2 by CX-MS

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

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