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Leucine repeat rich kinase 2

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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
#1
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
#2
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
#3
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
#4
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...
September 6, 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
#5
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
#6
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
#7
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
#8
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
https://www.readbyqxmd.com/read/28802631/the-design-and-sar-of-a-novel-series-of-2-aminopyridine-based-lrrk2-inhibitors
#9
Garrick P Smith, Lassina Badolo, Victoria Chell, I-Jen Chen, Kenneth Vielsted Christensen, Laurent David, Justus Alfred Daechsel, Morten Hentzer, Martin Christian Herzig, Gitte Kobberøe Mikkelsen, Stephen P Watson, Douglas S Williamson
Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1 (MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was identified.
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28774425/discovery-of-5-substituent-n-arylbenzamide-derivatives-as-potent-selective-and-orally-bioavailable-lrrk2-inhibitors
#10
Xiao Ding, Xuedong Dai, Kai Long, Cheng Peng, Daniele Andreotti, Paul Bamborough, Andrew J Eatherton, Colin Edge, Karamjit S Jandu, Paula L Nichols, Oliver J Philps, Luigi Piero Stasi, Zehong Wan, Jia-Ning Xiang, Kelly Dong, Pamela Dossang, Ming-Hsun Ho, Yi Li, Lucy Mensah, Xiaoming Guan, Alastair D Reith, Feng Ren
Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson's disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability.
July 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28764903/achieving-neuroprotection-with-lrrk2-kinase-inhibitors-in-parkinson-disease
#11
REVIEW
Andrew B West
In the translation of discoveries from the laboratory to the clinic, the track record in developing disease-modifying therapies in neurodegenerative disease is poor. A carefully designed development pipeline built from discoveries in both pre-clinical models and patient populations is necessary to optimize the chances for success. Genetic variation in the leucine-rich repeat kinase two gene (LRRK2) is linked to Parkinson disease (PD) susceptibility. Pathogenic mutations, particularly those in the LRRK2 GTPase (Roc) and COR domains, increase LRRK2 kinase activities in cells and tissues...
July 29, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28751896/proteomics-coupled-with-metabolite-and-cell-wall-profiling-reveal-metabolic-processes-of-a-developing-rice-stem-internode
#12
Fan Lin, Brad J Williams, Padmavathi A V Thangella, Adam Ladak, Athena A Schepmoes, Hernando J Olivos, Kangmei Zhao, Stephen J Callister, Laura E Bartley
Internodes of grass stems function in mechanical support, transport, and, in some species, are a major sink organ for carbon in the form of cell wall polymers. This study reports cell wall composition, proteomic, and metabolite analyses of the rice elongating internode. Cellulose, lignin, and xylose increase as a percentage of cell wall material along eight segments of the second rice internode (internode II) at booting stage, from the younger to the older internode segments, indicating active cell wall synthesis...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28723952/evidence-for-prehistoric-origins-of-the-g2019s-mutation-in-the-north-african-berber-population
#13
Rafiqua Ben El Haj, Ayyoub Salmi, Wafa Regragui, Ahmed Moussa, Naima Bouslam, Houyam Tibar, Ali Benomar, Mohamed Yahyaoui, Ahmed Bouhouche
The most common cause of the monogenic form of Parkinson's disease known so far is the G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene. Its frequency varies greatly among ethnic groups and geographic regions ranging from less than 0.1% in Asia to 40% in North Africa. This mutation has three distinct haplotypes; haplotype 1 being the oldest and most common. Recent studies have dated haplotype 1 of the G2019S mutation to about 4000 years ago, but it remains controversial whether the mutation has a Near-Eastern or Moroccan-Berber ancestral origin...
2017: PloS One
https://www.readbyqxmd.com/read/28720718/phosphorylation-of-amyloid-precursor-protein-by-mutant-lrrk2-promotes-aicd-activity-and-neurotoxicity-in-parkinson-s-disease
#14
Zhong-Can Chen, Wei Zhang, Ling-Ling Chua, Chou Chai, Rong Li, Lin Lin, Zhen Cao, Dario C Angeles, Lawrence W Stanton, Jian-He Peng, Zhi-Dong Zhou, Kah-Leong Lim, Li Zeng, Eng-King Tan
Mutations in LRRK2, which encodes leucine-rich repeat kinase 2, are the most common genetic cause of familial and sporadic Parkinson's disease (PD), a degenerative disease of the central nervous system that causes impaired motor function and, in advanced stages, dementia. Dementia is a common symptom of another neurodegenerative disease, Alzheimer's disease, and research suggests that there may be pathophysiological and genetic links between the two diseases. Aggregates of β amyloid [a protein produced through cleavage of amyloid precursor protein (APP)] are seen in both diseases and in PD patients carrying G2019S-mutant LRRK2...
July 18, 2017: Science Signaling
https://www.readbyqxmd.com/read/28710481/the-lrrk2-g2385r-variant-is-a-partial-loss-of-function-mutation-that-affects-synaptic-vesicle-trafficking-through-altered-protein-interactions
#15
Maria Dolores Perez Carrion, Silvia Marsicano, Federica Daniele, Antonella Marte, Francesca Pischedda, Eliana Di Cairano, Ester Piovesana, Felix von Zweydorf, Elisabeth Kremmer, Christian Johannes Gloeckner, Franco Onofri, Carla Perego, Giovanni Piccoli
Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28700714/genome-wide-re-sequencing-of-newly-developed-rice-lines-from-common-wild-rice-oryza-rufipogon-griff-for-the-identification-of-nbs-lrr-genes
#16
Wen Liu, Fozia Ghouri, Hang Yu, Xiang Li, Shuhong Yu, Muhammad Qasim Shahid, Xiangdong Liu
Common wild rice (Oryza rufipogon Griff.) is an important germplasm for rice breeding, which contains many resistance genes. Re-sequencing provides an unprecedented opportunity to explore the abundant useful genes at whole genome level. Here, we identified the nucleotide-binding site leucine-rich repeat (NBS-LRR) encoding genes by re-sequencing of two wild rice lines (i.e. Huaye 1 and Huaye 2) that were developed from common wild rice. We obtained 128 to 147 million reads with approximately 32.5-fold coverage depth, and uniquely covered more than 89...
2017: PloS One
https://www.readbyqxmd.com/read/28698826/expression-refolding-and-spectroscopic-characterization-of-fibronectin-type-iii-fniii-homology-domains-derived-from-human-fibronectin-leucine-rich-transmembrane-protein-flrt-1-2-and-3
#17
Lila Yang, Maria Hansen Falkesgaard, Peter Waaben Thulstrup, Peter Schledermann Walmod, Leila Lo Leggio, Kim Krighaar Rasmussen
The fibronectin leucine rich transmembrane (FLRT) protein family consists in humans of 3 proteins, FLRT1, -2, and -3. The FLRT proteins contain two extracellular domains separated by an unstructured linker. The most membrane distal part is a leucine rich repeat (LRR) domain responsible for both cis- and trans-interactions, whereas the membrane proximal part is a fibronectin type III (FnIII) domain responsible for a cis-interaction with members of the fibroblast growth factor receptor 1 (FGFR1) family, which results in FGFR tyrosine kinase activation...
2017: PeerJ
https://www.readbyqxmd.com/read/28697798/a-proteomic-analysis-of-lrrk2-binding-partners-reveals-interactions-with-multiple-signaling-components-of-the-wnt-pcp-pathway
#18
Alena Salašová, Chika Yokota, David Potěšil, Zbyněk Zdráhal, Vítězslav Bryja, Ernest Arenas
BACKGROUND: Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/β-catenin signaling via its interaction with the β-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients...
July 11, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28688273/leucine-rich-repeat-kinase-2-lrrk2-inhibitors-based-on-indolinone-scaffold-potential-pro-neurogenic-agents
#19
Irene G Salado, Josefa Zaldivar-Diez, Víctor Sebastián-Pérez, Lingling Li, Larissa Geiger, Silvia González, Nuria E Campillo, Carmen Gil, Aixa V Morales, Daniel I Perez, Ana Martinez
Leucine-rich repeat kinase 2 (LRRK2) is one of the most pursued targets for Parkinson's disease (PD) therapy. Moreover, it has recently described its role in regulating Wnt signaling and thus, it may be involved in adult neurogenesis. This new hypothesis could give rise to double disease-modifying agents firstly by the benefits of inhibiting LRRK2 and secondly by promoting adult neurogenesis. Herein we report, the design, synthesis, biological evaluation, SAR and potential binding mode of indoline-like LRRK2 inhibitors and their preliminary neurogenic effect in neural precursor cells isolated from adult mice ventricular-subventricular zone...
June 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28683740/using-kasp-technique-to-screen-lrrk2-g2019s-mutation-in-a-large-tunisian-cohort
#20
Zied Landoulsi, Sawssan Benromdhan, Mouna Ben Djebara, Mariem Damak, Hamza Dallali, Rym Kefi, Sonia Abdelhak, Amina Gargouri-Berrechid, Chokri Mhiri, Riadh Gouider
BACKGROUND: In North African populations, G2019S mutation in LRRK2 gene, encoding for the leucine-rich repeat kinase 2, is the most prevalent mutation linked to familial and sporadic Parkinson's disease (PD). Early detection of G2019S by fast genetic testing is very important to guide PD's diagnosis and support patients and their family caregivers for better management of their life according to disease's evolution. METHODS: In our study, a genetic PD's diagnosis tool was developed for large scale genotyping using Kompetitive Allele Specific PCR (KASP) technology...
July 6, 2017: BMC Medical Genetics
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