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Leucine repeat rich kinase 2

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https://www.readbyqxmd.com/read/29150546/differential-regulation-of-two-tiered-plant-immunity-and-sexual-reproduction-by-anxur-receptor-like-kinases
#1
Hyunggon Mang, Baomin Feng, Zhangjian Hu, Aurelien Boisson-Dernier, Christina Franck, Xiangzong Meng, Yanyan Huang, Jinggeng Zhou, Guangyuan Xu, Taotao Wang, Libo Shan, Ping He
Plants have evolved two tiers of immune receptors to detect infections: cell surface-resident pattern recognition receptors (PRRs) that sense microbial signatures and intracellular nucleotide-binding domain leucine-rich repeat (NLR) proteins that recognize pathogen effectors. How PRRs and NLRs interconnect and activate the specific and overlapping plant immune responses remains elusive. A genetic screen for components controlling plant immunity identified ANXUR1 (ANX1), a malectin-like domain-containing receptor-like kinase, together with its homolog ANX2, as important negative regulators of both PRR- and NLR-mediated immunity in Arabidopsis thaliana...
November 17, 2017: Plant Cell
https://www.readbyqxmd.com/read/29129681/decreased-sirtuin-deacetylase-activity-in-lrrk2-g2019s-ipsc-derived-dopaminergic-neurons
#2
Andrew J Schwab, Samantha L Sison, Michael R Meade, Katarzyna A Broniowska, John A Corbett, Allison D Ebert
Mitochondrial changes have long been implicated in the pathogenesis of Parkinson's disease (PD). The glycine to serine mutation (G2019S) in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause for PD and has been shown to impair mitochondrial function and morphology in multiple model systems. We analyzed mitochondrial function in LRRK2 G2019S induced pluripotent stem cell (iPSC)-derived neurons to determine whether the G2019S mutation elicits similar mitochondrial deficits among central and peripheral nervous system neuron subtypes...
October 31, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29109411/structural-basis-for-receptor-recognition-of-pollen-tube-attraction-peptides
#3
Xiaoxiao Zhang, Weijia Liu, Takuya T Nagae, Hidenori Takeuchi, Heqiao Zhang, Zhifu Han, Tetsuya Higashiyama, Jijie Chai
Transportation of the immobile sperms directed by pollen tubes to the ovule-enclosed female gametophytes is important for plant sexual reproduction. The defensin-like (DEFL) cysteine-rich peptides (CRPs) LUREs play an essential role in pollen tube attraction to the ovule, though their receptors still remain controversial. Here we provide several lines of biochemical evidence showing that the extracellular domain of the leucine-rich repeat receptor kinase (LRR-RK) PRK6 from Arabidopsis thaliana directly interacts with AtLURE1 peptides...
November 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/29038245/mitochondrial-calcium-dysregulation-contributes-to-dendrite-degeneration-mediated-by-pd-lbd-associated-lrrk2-mutants
#4
Manish Verma, Jason Callio, P Anthony Otero, Israel Sekler, Zachary P Wills, Charleen T Chu
Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs prior to the well-characterized phenotype of dendritic shortening...
October 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29023112/design-of-leucine-rich-repeat-kinase-2-lrrk2-inhibitors-using-a-crystallographic-surrogate-derived-from-checkpoint-kinase-1-chk1
#5
Douglas S Williamson, Garrick P Smith, Pamela Acheson-Dossang, Simon T Bedford, Victoria Chell, I-Jen Chen, Justus C A Daechsel, Zoe Daniels, Laurent David, Pawel Dokurno, Morten Hentzer, Martin C Herzig, Roderick E Hubbard, Jonathan D Moore, James B Murray, Samantha Newland, Stuart C Ray, Terry Shaw, Allan E Surgenor, Lindsey Terry, Kenneth Thirstrup, Yikang Wang, Kenneth V Christensen
Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors...
October 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28985749/correction-to-leucine-rich-repeat-kinase-2-lrrk2-phosphorylates-p53-and-induces-p21-waf1-cip1-expression
#6
Dong Hwan Ho, Hyejung Kim, Jisun Kim, Hyuna Sim, Hyunjun Ahn, Janghwan Kim, Hyemyung Seo, Kwang Chul Chung, Bum-Joon Park, Ilhong Son, Wongi Seol
No abstract text is available yet for this article.
October 6, 2017: Molecular Brain
https://www.readbyqxmd.com/read/28973664/lrrk2-g2019s-induced-mitochondrial-dna-damage-is-lrrk2-kinase-dependent-and-inhibition-restores-mtdna-integrity-in-parkinson-s-disease
#7
Evan H Howlett, Nicholas Jensen, Frances Belmonte, Faria Zafar, Xiaoping Hu, Jillian Kluss, Birgitt Schüle, Brett A Kaufman, J T Greenamyre, Laurie H Sanders
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with increased risk for developing Parkinson's disease (PD). Previously, we found that LRRK2 G2019S mutation carriers have increased mitochondrial DNA (mtDNA) damage and after zinc finger nuclease-mediated gene mutation correction, mtDNA damage was no longer detectable. While the mtDNA damage phenotype can be unambiguously attributed to the LRRK2 G2019S mutation, the underlying mechanism(s) is unknown. Here, we examine the role of LRRK2 kinase function in LRRK2 G2019S-mediated mtDNA damage, using both genetic and pharmacological approaches in cultured neurons and PD patient-derived cells...
November 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28973420/lrrk2-interacts-with-atm-and-regulates-mdm2-p53-cell-proliferation-axis-in-response-to-genotoxic-stress
#8
Zhongcan Chen, Zhen Cao, Wei Zhang, Minxia Gu, Zhi Dong Zhou, Baojie Li, Jing Li, Eng King Tan, Li Zeng
Pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations are recognized as the most common cause of familial Parkinson's disease in certain populations. Recently, LRRK2 mutations were shown to be associated with a higher risk of hormone-related cancers. However, how LRRK2 itself contributes to cancer risk remains unknown. DNA damage causes cancer, and DNA damage responses are among the most important pathways in cancer biology. To understand the role of LRRK2 in DNA damage response pathway, we induced DNA damage by applying genotoxic stress to the cells with Adriamycin...
November 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28972154/neutrophil-microparticle-production-and-inflammasome-activation-by-hyperglycemia-due-to-cytoskeletal-instability
#9
Stephen R Thom, Veena M Bhopale, Kevin Yu, Weiliang Huang, Maureen A Kane, David J Margolis
Microparticles are lipid bilayer-enclosed vesicles produced by cells under oxidative stress. MP production is elevated in patients with diabetes, but the underlying cellular mechanisms are poorly understood. We hypothesized that raising glucose above the physiological level of 5.5 mm would stimulate leukocytes to produce MPs and activate the nucleotide-binding domain, leucine-rich repeat pyrin domain-containing 3 (NLRP3) inflammasome. We found that when incubated in buffer with up to 20 mm glucose, human and murine neutrophils, but not monocytes, generate progressively more MPs with high interleukin (IL)-1β content...
November 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28972042/transmembrane-and-coiled-coil-domain-1-impairs-the-akt-signaling-pathway-in-urinary-bladder-urothelial-carcinoma-a-characterization-of-a-tumor-suppressor
#10
Chien-Feng Li, Wen-Ren Wu, Ti-Chun Chan, Yu-Hui Wang, Lih-Ren Chen, Wen-Jeng Wu, Bi-Wen Yeh, Shih-Shin Liang, Yow-Ling Shiue
PURPOSE: Urinary bladder urothelial carcinoma (UBUC) is a common malignant disease in developed countries. Cell cycle dysregulation resulting in uncontrolled cell proliferation has been associated with UBUC development. This study aimed to explore the roles of TMCO1 in UBUCs. EXPERIMENTAL DESIGN: Data mining, branched DNA assay, immunohistochemistry, xenograft, cell culture, quantitative RT-PCR, immunoblotting, stable and transient transfection, lentivirus production and stable knockdown, cell cycle, cell viability and proliferation, soft agar, wound healing, transwell migration and invasion, co-immunoprecipitation, immunocytochemistry, AKT serine/threonine kinase (AKT) activity assays and site-directed mutagenesis were used to study TMCO1 involvement in vivo and in vitro...
September 29, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28958936/suppression-of-neuroinflammation-by-matrix-metalloproteinase-8-inhibitor-in-aged-normal-and-lrrk2-g2019s-parkinson-s-disease-model-mice-challenged-with-lipopolysaccharide
#11
Jisun Kim, Yeon-Hui Jeong, Eun-Jung Lee, Jin-Sun Park, Hyemyung Seo, Hee-Sun Kim
Microglial priming is caused by aging and neurodegenerative diseases, and is characterized by an exaggerated microglial inflammatory response to secondary and sub-threshold challenges. In the present study, we examined the effects of the matrix metalloproteinase-8 (MMP-8) inhibitor (M8I) on the brain of aged normal and leucine-rich repeat kinase 2 (LRRK2) G2019S Parkinson's disease (PD) model mice systemically stimulated with lipopolysaccharide (LPS). The results indicated that Iba-1 positive microglia and GFAP-positive astrocytes, which were increased by LPS, significantly decreased by M8I in aged normal and PD model mice...
November 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28941828/fatigue-correlates-with-lrrk2-g2385r-variant-in-chinese-parkinson-s-disease-patients
#12
Rao Fu, Shi-Shuang Cui, Juan-Juan Du, Ya-Chao He, Chao Gao, Pei Huang, Yi-Wei Qian, Xiao-Guang Luo, Sheng-Di Chen
INTRODUCTION: Fatigue is common in patients with Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) G2385R variant predisposes individuals to develop PD in China. The aim of this study was to evaluate whether the LRRK2 G2385R variant is associated with fatigue in patients with PD. METHODS: Fatigue was evaluated by the Parkinson Fatigue Scale (PFS) in 329 PD patients and 180 controls, a cut-off score of ≥3.3 was used to define the presence of fatigue...
September 18, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28938613/high-phlpp1-expression-levels-predicts-longer-time-of-acquired-resistance-to-egfr-tyrosine-kinase-inhibitors-in-patients-with-lung-adenocarcinoma
#13
Youyou Xie, Dongqing Lv, Wei Wang, Minhua Ye, Xiaofeng Chen, Haihua Yang
BACKGROUND: In spite of an initial good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in lung adenocarcinoma patients, resistance to treatment eventually occurs. Epidermal growth factor receptor (EGFR) activation stimulates Ras/Raf/Erk/MAPK and influences PI3K/Akt pathways, respectively. PHLPP negatively regulates PI3K/Akt and the RAF/RAS/ERK signaling pathways. Our study aimed to investigate the association between PH domain leucine-rich-repeats protein phosphatase (PHLPP) expression levels and the acquired resistance to EGFR TKIs in lung adenocarcinoma...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28918051/lrrk2-antisense-oligonucleotides-ameliorate-%C3%AE-synuclein-inclusion-formation-in-a-parkinson-s-disease-mouse-model
#14
Hien Tran Zhao, Neena John, Vedad Delic, Karli Ikeda-Lee, Aneeza Kim, Andreas Weihofen, Eric E Swayze, Holly B Kordasiewicz, Andrew B West, Laura A Volpicelli-Daley
No treatments exist to slow or halt Parkinson's disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one of the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 inhibition have demonstrated promise in blocking α-synuclein (α-syn) pathology. However, LRRK2 kinase inhibitors may reduce LRRK2 activity in several tissues and induce systemic phenotypes in the kidney and lung that are undesirable. Here, we test whether antisense oligonucleotides (ASOs) provide an alternative therapeutic strategy, as they can be restricted to the CNS and provide a stable, long-lasting reduction of protein throughout the brain...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28901623/new-link-between-parkinson-s-and-alzheimer-s-research-uncovers-the-role-of-mutant-leucine-rich-repeat-kinase-2-and-amyloid-precursor-protein
#15
Kaveh Same, Farzaneh Ghazi Sherbaf, Mohammad Hadi Aarabi
No abstract text is available yet for this article.
September 13, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28888991/lrrk2-functions-as-a-scaffolding-kinase-of-ask1-mediated-neuronal-cell-death
#16
Ji-Hye Yoon, Jung-Soon Mo, Mi-Yeon Kim, Eun-Jung Ann, Ji-Seon Ahn, Eun-Hye Jo, Hye-Jin Lee, Young Chul Lee, Wongi Seol, Sergiy M Yarmoluk, Thomas Gasser, Philipp J Kahle, Guang-Hui Liu, Juan Carlos Izpisua Belmonte, Hee-Sae Park
Leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein, is a key causative factor in Parkinson's disease (PD). Identification of novel substrates and the molecular mechanisms underlying the effects of LRRK2 are essential for understanding the pathogenesis of PD. In this study, we showed that LRRK2 played an important role in neuronal cell death by directly phosphorylating and activating apoptosis signal-regulating kinase 1 (ASK1). LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site...
December 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28860483/selective-lrrk2-kinase-inhibition-reduces-phosphorylation-of-endogenous-rab10-and-rab12-in-human-peripheral-mononuclear-blood-cells
#17
Kenneth Thirstrup, Justus C Dächsel, Felix S Oppermann, Douglas S Williamson, Garrick P Smith, Karina Fog, Kenneth V Christensen
Genetic variation in the leucine-rich repeat kinase 2 (LRRK2) gene is associated with risk of familial and sporadic Parkinson's disease (PD). To support clinical development of LRRK2 inhibitors as disease-modifying treatment in PD biomarkers for kinase activity, target engagement and kinase inhibition are prerequisite tools. In a combined proteomics and phosphoproteomics study on human peripheral mononuclear blood cells (PBMCs) treated with the LRRK2 inhibitor Lu AF58786 a number of putative biomarkers were identified...
August 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28859611/transcript-profiling-of-genes-expressed-during-fibre-development-in-diploid-cotton-gossypium-arboreum-l
#18
Atul S Hande, Ishwarappa S Katageri, Mangesh P Jadhav, Sateesh Adiger, Savita Gamanagatti, Kethireddy Venkata Padmalatha, Gurusamy Dhandapani, Mogilicherla Kanakachari, Polumetla Ananda Kumar, Vanga Siva Reddy
BACKGROUND: Cotton fibre is a single cell and it is one of the best platforms for unraveling the genes express during various stages of fibre development. There are reports devoted to comparative transcriptome study on fiber cell initiation and elongation in tetraploid cultivated cotton. However, in the present investigation, comparative transcriptome study was made in diploid cultivated cotton using isogenic fuzzy-lintless (Fl) and normal fuzzy linted (FL) lines belong to Gossypium arboreum, diploid species at two stages, 0 and 10 dpa (days post anthesis), using Affymetrix cotton GeneChip genome array...
August 31, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28819229/cryo-em-analysis-of-homodimeric-full-length-lrrk2-and-lrrk1-protein-complexes
#19
Kushal Sejwal, Mohamed Chami, Hervé Rémigy, Renée Vancraenenbroeck, William Sibran, Rosmarie Sütterlin, Paul Baumgartner, Robert McLeod, Marie-Christine Chartier-Harlin, Veerle Baekelandt, Henning Stahlberg, Jean-Marc Taymans
Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein implicated in the pathogenesis of both familial and sporadic Parkinson's disease (PD), and currently one of the most promising therapeutic targets for drug design in Parkinson's disease. In contrast, LRRK1, the closest homologue to LRRK2, does not play any role in PD. Here, we use cryo-electron microscopy (cryo-EM) and single particle analysis to gain structural insight into the full-length dimeric structures of LRRK2 and LRRK1. Differential scanning fluorimetry-based screening of purification buffers showed that elution of the purified LRRK2 protein in a high pH buffer is beneficial in obtaining high quality cryo-EM images...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28813015/transcriptional-responses-of-creeping-bentgrass-to-2-3-butanediol-a-bacterial-volatile-compound-bvc-analogue
#20
Yi Shi, Kuiju Niu, Bingru Huang, Wenhui Liu, Huiling Ma
Bacterial volatile compounds (BVCs) have been reported to enhance plant growth and elicit plant defenses against fungal infection and insect damage. The objective of this study was to determine transcriptomic changes in response to synthetic BVC that could be associated with plant resistance to Rhizoctonia solani in creeping bentgrass. The 2,3-butanediol (BD) (250 µM) was sprayed on creeping bentgrass leaves grown in jam jars. The result showed that synthetic BD induced plant defense against R. solani for creeping bentgrass...
August 16, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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