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Leucine repeat rich kinase 2

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https://www.readbyqxmd.com/read/29789389/lrrk2-is-a-negative-regulator-of-mycobacterium-tuberculosis-phagosome-maturation-in-macrophages
#1
Anetta Härtlova, Susanne Herbst, Julien Peltier, Angela Rodgers, Orsolya Bilkei-Gorzo, Antony Fearns, Brian D Dill, Heyne Lee, Rowan Flynn, Sally A Cowley, Paul Davies, Patrick A Lewis, Ian G Ganley, Jennifer Martinez, Dario R Alessi, Alastair D Reith, Matthias Trost, Maximiliano G Gutierrez
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 complex and Rubicon to the phagosome in macrophages...
May 22, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29760073/regulation-of-myeloid-cell-phagocytosis-by-lrrk2-via-wave2-complex-stabilization-is-altered-in-parkinson-s-disease
#2
Kwang Soo Kim, Paul C Marcogliese, Jungwoo Yang, Steve M Callaghan, Virginia Resende, Elizabeth Abdel-Messih, Connie Marras, Naomi P Visanji, Jana Huang, Michael G Schlossmacher, Laura Trinkle-Mulcahy, Ruth S Slack, Anthony E Lang, David S Park
Leucine-rich repeat kinase 2 ( LRRK2 ) has been implicated in both familial and sporadic Parkinson's disease (PD), yet its pathogenic role remains unclear. A previous screen in Drosophila identified Scar/WAVE (Wiskott-Aldrich syndrome protein-family verproline) proteins as potential genetic interactors of LRRK2 Here, we provide evidence that LRRK2 modulates the phagocytic response of myeloid cells via specific modulation of the actin-cytoskeletal regulator, WAVE2. We demonstrate that macrophages and microglia from LRRK2-G2019S PD patients and mice display a WAVE2-mediated increase in phagocytic response, respectively...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29738771/mir-141-3p-is-upregulated-in-esophageal-squamous-cell-carcinoma-and-targets-pleckstrin-homology-domain-leucine-rich-repeat-protein-phosphatase-2-a-negative-regulator-of-the-pi3k-akt-pathway
#3
Osamu Ishibashi, Ichiro Akagi, Yota Ogawa, Takashi Inui
The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is frequently activated in various human cancers and plays essential roles in their development and progression. Accumulating evidence suggests that dysregulated expression of microRNAs (miRNAs) is closely associated with cancer progression and metastasis. Here, we focused on miRNAs that could regulate genes related to the PI3K/AKT pathway in esophageal squamous cell carcinoma (ESCC). To identify upregulated miRNAs and their possible target genes in ESCC, we performed microarray-based integrative analyses of miRNA and mRNA expression levels in three human ESCC cell lines and a normal esophageal epithelial cell line...
May 11, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29735985/the-serk3-elongated-allele-defines-a-role-for-bir-ectodomains-in-brassinosteroid-signalling
#4
Ulrich Hohmann, Joël Nicolet, Andrea Moretti, Ludwig A Hothorn, Michael Hothorn
The leucine-rich repeat receptor kinase (LRR-RK) BRASSINOSTEROID INSENSITIVE 1 (BRI1) requires a shape-complementary SOMATIC EMBRYOGENESIS RECEPTOR KINASE (SERK) co-receptor for brassinosteroid sensing and receptor activation 1 . Interface mutations that weaken the interaction between receptor and co-receptor in vitro reduce brassinosteroid signalling responses 2 . The SERK3 elongated (elg) allele3-5 maps to the complex interface and shows enhanced brassinosteroid signalling, but surprisingly no tighter binding to the BRI1 ectodomain in vitro...
May 7, 2018: Nature Plants
https://www.readbyqxmd.com/read/29735704/lrrk2-phosphorylation-of-auxilin-mediates-synaptic-defects-in-dopaminergic-neurons-from-patients-with-parkinson-s-disease
#5
Maria Nguyen, Dimitri Krainc
Recently identified Parkinson's disease (PD) genes involved in synaptic vesicle endocytosis, such as DNAJC6 (auxilin), have further implicated synaptic dysfunction in PD pathogenesis. However, how synaptic dysfunction contributes to the vulnerability of human dopaminergic neurons has not been previously explored. Here, we demonstrate that commonly mutated, PD-linked leucine-rich repeat kinase 2 (LRRK2) mediates the phosphorylation of auxilin in its clathrin-binding domain at Ser627. Kinase activity-dependent LRRK2 phosphorylation of auxilin led to differential clathrin binding, resulting in disrupted synaptic vesicle endocytosis and decreased synaptic vesicle density in LRRK2 patient-derived dopaminergic neurons...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29726283/lactobacillus-plantarum-is-10506-activates-intestinal-stem-cells-in-a-rodent-model
#6
A F Athiyyah, A Darma, R Ranuh, W Riawan, A Endaryanto, F A Rantam, I S Surono, S M Sudarmo
This study investigated the probiotic effect of Lactobacillus plantarum IS-10506 in activating and regenerating leucine-rich repeat-containing G-protein-coupled receptor (Lgr)5- and B lymphoma Moloney murine leukaemia virus insertion region (Bmi)1-expressing intestinal stem cells in rodents following Escherichia coli serotype 055:B5 lipopolysaccharide (LPS) exposure. Male Sprague-Dawley rats (n=64) were randomised into control (KN), LPS (KL), probiotic + LPS (KL-Pr), and sequential probiotic + LPS + probiotic (KPR-7L) groups...
May 4, 2018: Beneficial Microbes
https://www.readbyqxmd.com/read/29719501/acetylome-in-human-fibroblasts-from-parkinson-s-disease-patients
#7
Sokhna M S Yakhine-Diop, Mario Rodríguez-Arribas, Guadalupe Martínez-Chacón, Elisabet Uribe-Carretero, Rubén Gómez-Sánchez, Ana Aiastui, Adolfo López de Munain, José M Bravo-San Pedro, Mireia Niso-Santano, Rosa A González-Polo, José M Fuentes
Parkinson's disease (PD) is a multifactorial neurodegenerative disorder. The pathogenesis of this disease is associated with gene and environmental factors. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of familial and sporadic PD. Moreover, posttranslational modifications, including protein acetylation, are involved in the molecular mechanism of PD. Acetylation of lysine proteins is a dynamic process that is modulated in PD. In this descriptive study, we characterized the acetylated proteins and peptides in primary fibroblasts from idiopathic PD (IPD) and genetic PD harboring G2019S or R1441G LRRK2 mutations...
2018: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29717018/medicago-plants-control-nodulation-by-regulating-proteolysis-of-the-receptor-like-kinase-dmi2
#8
Huairong Pan, Dong Wang
Plants use receptor-like kinases to monitor environmental changes and transduce signals into plant cells. The Medicago truncatula DOES NOT MAKE INFECTIONS 2 (DMI2) protein functions as a co-receptor of rhizobial signals to initiate nodule development and rhizobial infection during nitrogen-fixing symbiosis, but the mechanisms regulating DMI2 protein level and folding are still unknown. Here we report that DMI2 protein abundance changes during nitrogen-fixing symbiosis. DMI2 accumulates in the nodules and is induced by rhizobia treatment through a posttranscriptional process...
May 1, 2018: Plant Physiology
https://www.readbyqxmd.com/read/29705795/leucine-rich-repeat-kinase-2-in-parkinson-s-disease-updated-from-pathogenesis-to-potential-therapeutic-target
#9
Jinhua Chen, Ying Chen, Jiali Pu
BACKGROUND: Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. SUMMARY: Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment...
April 27, 2018: European Neurology
https://www.readbyqxmd.com/read/29700116/comparative-analysis-of-parkinson-s-disease-associated-genes-reveals-altered-survival-and-bioenergetics-of-parkin-deficient-dopamine-neurons-in-mice
#10
Nicolas Giguere, Consiglia Pacelli, Caroline Saumure, Marie-Josee Bourque, Diana Matheoud, Daniel Levesque, Ruth S Slack, David S Park, Louis-Eric Trudeau
Many mutations in genes encoding proteins such as parkin, PTEN-induced putative kinase 1 (PINK1), protein deglycase DJ-1 (DJ-1 or PARK7), leucine-rich repeat kinase 2 (LRRK2), and α-synuclein have been linked to familial forms of Parkinson's disease (PD). The consequences of these mutations, such as altered mitochondrial function and pathological protein aggregation, are starting to be better understood. However, little is known about the mechanisms explaining why alterations in such diverse cellular mechanisms lead to the selective loss of dopamine (DA) neurons in the substantia nigra (SNc) in the brain of individuals with PD...
April 26, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29693156/downregulation-of-lgr6-inhibits-proliferation-and-invasion-and-increases-apoptosis-in-human-colorectal-cancer
#11
Fei Wang, Chun-Qian Dai, Li-Rong Zhang, Cao Bing, Jun Qin, Yi-Fei Liu
The aim of the present study was to analyze the role of leucine‑rich repeat‑containing G‑protein coupled receptor 6 (Lgr6) in the proliferation and invasion of colorectal cancer (CRC) cells, and to investigate its possible mechanisms. The expression of Lgr6 in CRC tissues was observed by real time‑quantitative polymerase chain reaction and western blotting. Then cell viability, apoptosis and cell invasion was measured by MTT, flow cytometry or Matrigel‑Transwell system, respectively in CRC cells after transfected with Lgr6 siRNA or Lgr6 vector...
April 18, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29680709/parkinson-s-disease-like-burst-firing-activity-in-subthalamic-nucleus-induced-by-aav-%C3%AE-synuclein-is-normalized-by-lrrk2-modulation
#12
Michael Aagaard Andersen, Kenneth Vielsted Christensen, Lassina Badolo, Garrick Paul Smith, Ross Jeggo, Poul Henning Jensen, Kathrine Just Andersen, Florence Sotty
Parkinson's disease (PD) affects motor function through degenerative processes and synaptic transmission impairments in the basal ganglia. None of the treatments available delays or stops the progression of the disease. While α-synuclein pathological accumulation represents a hallmark of the disease in its idiopathic form, leucine rich repeat kinase 2 (LRRK2) is genetically associated with familial and sporadic forms of PD. The genetic information suggests that LRRK2 kinase activity plays a role in the pathogenesis of the disease...
April 19, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29665080/clustering-of-motor-and-nonmotor-traits-in-leucine-rich-repeat-kinase-2-g2019s-parkinson-s-disease-nonparkinsonian-relatives-a-multicenter-family-study
#13
Tiago A Mestre, Claustre Pont-Sunyer, Farah Kausar, Naomi P Visanji, Taneera Ghate, Barbara S Connolly, Carmen Gasca-Salas, Drew S Kern, Jennifer Jain, Elizabeth J Slow, Achinoam Faust-Socher, Meike Kasten, Pettarusp M Wadia, Cindy Zadikoff, Prakash Kumar, Ronald M de Bie, Teri Thomsen, Anthony E Lang, Birgitt Schüle, Christine Klein, Eduardo Tolosa, Connie Marras
OBJECTIVES: The objective of this study was to determine phenotypic features that differentiate nonparkinsonian first-degree relatives of PD leucine-rich repeat kinase 2 (LRRK2) G2019S multiplex families, regardless of carrier status, from healthy controls because nonparkinsonian individuals in multiplex families seem to share a propensity to present neurological features. METHODS: We included nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases and unrelated healthy controls participating in established multiplex family LRRK2 cohorts...
April 17, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29628444/ph-domain-leucine-rich-repeat-protein-phosphatase-2-phlpp2-regulates-g-protein-coupled-receptor-kinase-5-grk5-induced-cardiac-hypertrophy-in-vitro
#14
Szu-Tsen Yeh, Cristina M Zambrano, Walter J Koch, Nicole H Purcell
PH domain leucine-rich repeat protein phosphatase (PHLPP) is a serine/threonine phosphatase that has been shown to regulate cell growth and survival through dephosphorylation of several members of the AGC family of kinases. G-protein coupled receptor kinase 5 (GRK5) is an AGC kinase that regulates phenylephrine (PE) induced cardiac hypertrophy through its non-canonical function of directly targeting proteins to the nucleus to regulate transcription. Here we investigated the possibility that the PHLPP2 isoform can regulate GRK5 induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes (NRVMs)...
April 8, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29626488/berberine-induced-modulation-of-phlpp2-akt-mst1-kinase-signaling-is-coupled-with-mitochondrial-impairment-and-hepatoma-cell-death
#15
Sugandh Saxena, Shatrunajay Shukla, Poonam Kakkar
Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) has been known to exert tumor suppressive activity for long without much knowledge about its regulation and implications. Protein kinase B (Akt), Protein kinase C (PKC) and Ribosomal protein S6 Kinase (S6K) are known downtargets of PHLPP2, regulating a plethora of life processes viz. cell growth, survival and evasion from apoptosis. Present study decoded the crucial role of PHLPP2 in inducing apoptosis by its interaction with the newly found binding partner Mammalian sterile 20-like kinase 1 (Mst1) in berberine (BBR)-treated human hepatoma cells...
April 4, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29593234/case-control-analysis-of-lrrk2-protective-variants-in-essential-tremor
#16
Adeline S L Ng, Ebonne Y L Ng, Yi Jayne Tan, Kumar M Prakash, Wing Lok Au, Louis C S Tan, Eng-King Tan
Co-existence of Parkinson's disease (PD) and essential tremor (ET) may reflect overlapping pathophysiology underlying both conditions. Furthermore, PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations may present with ET-like features, suggesting the possibility of common genetic underpinnings. Two common LRRK2 variants, R1398H and N551K, have been shown to be protective in multiple PD cohorts. We hypothesized that R1398H and N551K may show a similar effect in ET. In a case-control study involving 3198 subjects (2680 controls and 518 ET cases), R1398H was detected in 16...
March 28, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29581511/a-group-of-receptor-kinases-are-essential-for-clavata-signalling-to-maintain-stem-cell-homeostasis
#17
Chong Hu, Yafen Zhu, Yanwei Cui, Kaili Cheng, Wan Liang, Zhuoyun Wei, Mingsong Zhu, Hongju Yin, Li Zeng, Ya Xiao, Minghui Lv, Jing Yi, Suiwen Hou, Kai He, Jia Li, Xiaoping Gou
Continuous organ initiation and outgrowth in plants relies on the proliferation and differentiation of stem cells maintained by the CLAVATA (CLV)-WUSCHEL (WUS) negative-feedback loop1-3 . Leucine-rich repeat receptor-like protein kinases (LRR-RLKs), including CLV1, BARELY ANY MERISTEMS and RECEPTOR-LIKE PROTEIN KINASE 2 (RPK2), a receptor-like protein CLV2 and a pseudokinase CORYNE (CRN) are involved in the perception of the CLV3 signal to repress WUS expression4-10 . WUS, a homeodomain transcription factor, in turn directly activates CLV3 expression and promotes stem cell activity in the shoot apical meristem11,12 ...
April 2018: Nature Plants
https://www.readbyqxmd.com/read/29567424/altered-intrinsic-brain-functional-connectivity-in-drug-na%C3%A3-ve-parkinson-s-disease-patients-with-lrrk2-mutations
#18
Yanbing Hou, Chunyan Luo, Jing Yang, Ruwei Ou, Wei Song, Yongping Chen, Qiyong Gong, Huifang Shang
BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) has been recently identified as a causative gene of Parkinson's disease (PD), and the LRRK2 R1628P and G2385R mutations are common in ethnic Han-Chinese PD patients. However, the pathogenic mechanism of LRRK2 mutations in PD remains largely unknown. METHODS: Resting-state functional MRI (fMRI) was used to assess the functional connectivity (FC) of the striatal subregions of 11 ethnic Han-Chinese drug-naïve PD patients with the LRRK2 R1628P or G2385R mutations, 11 ethnic Han-Chinese drug-naïve PD patients without such mutations, and 22 healthy control (HC) subjects...
March 19, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29563162/mtor-independent-alteration-in-ulk1-ser758-phosphorylation-following-chronic-lrrk2-kinase-inhibition
#19
Claudia Manzoni, Adamantios Mamais, Sybille Dihanich, Marc P M Soutar, Helene Plun-Favreau, Rina Bandopadhyay, Rosella Abeti, Paola Giunti, John Hardy, Mark R Cookson, Sharon A Tooze, Patrick A Lewis
Unc-51 Like Kinase 1 (ULK1) is a critical regulator of the biogenesis of autophagosomes, the central component of the catabolic macroautophagy pathway. Regulation of ULK1 activity is dependent upon several phosphorylation events acting to repress or activate the enzymatic function of this protein. Phosphorylation of Ser758 ULK1 has been linked to repression of autophagosome biogenesis and was thought to be exclusively dependent upon mTOR complex 1 kinase activity. In the present study, a novel regulation of Ser758 ULK1 phosphorylation is reported following prolonged inhibition of the Parkinson's disease linked protein leucine rich repeat kinase 2 (LRRK2)...
April 26, 2018: Bioscience Reports
https://www.readbyqxmd.com/read/29562525/rab10-phosphorylation-is-a-prominent-pathological-feature-in-alzheimer-s-disease
#20
Tingxiang Yan, Luwen Wang, Ju Gao, Sandra L Siedlak, Mikayla L Huntley, Pichet Termsarasab, George Perry, Shu G Chen, Xinglong Wang
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease...
2018: Journal of Alzheimer's Disease: JAD
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