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Leucine rich repeate kinase

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https://www.readbyqxmd.com/read/28819229/cryo-em-analysis-of-homodimeric-full-length-lrrk2-and-lrrk1-protein-complexes
#1
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
#2
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
#3
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.
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28783694/zbp1-dai-is-an-innate-sensor-of-influenza-virus-triggering-the-nlrp3-inflammasome-and-programmed-cell-death-pathways
#4
Teneema Kuriakose, Si Ming Man, R K Subbarao Malireddi, Rajendra Karki, Sannula Kesavardhana, David E Place, Geoffrey Neale, Peter Vogel, Thirumala-Devi Kanneganti
The interferon (IFN)-inducible protein Z-DNA binding protein 1 [ZBP1; also known as DNA-dependent activator of IFN regulatory factors (DAI) and DLM-1] was identified as a double-stranded DNA sensor, which instigates innate immune responses. However, this classification has been disputed, and whether ZBP1 functions as a pathogen sensor during an infection has remained unknown. We demonstrated ZBP1-mediated sensing of the influenza A virus (IAV) proteins NP and PB1, triggering cell death and inflammatory responses via the receptor-interacting protein kinase 1 (RIPK1)-RIPK3-caspase-8 axis...
August 12, 2016: Science Immunology
https://www.readbyqxmd.com/read/28774425/discovery-of-5-substituent-n-arylbenzamide-derivatives-as-potent-selective-and-orally-bioavailable-lrrk2-inhibitors
#5
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
#6
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
#7
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/28751691/a-deletion-affecting-an-lrr-rlk-gene-co-segregates-with-the-fruit-flat-shape-trait-in-peach
#8
Elena López-Girona, Yu Zhang, Iban Eduardo, José Ramón Hernández Mora, Konstantinos G Alexiou, Pere Arús, María José Aranzana
In peach, the flat phenotype is caused by a partially dominant allele in heterozygosis (Ss), fruits from homozygous trees (SS) abort a few weeks after fruit setting. Previous research has identified a SSR marker (UDP98-412) highly associated with the trait, found suitable for marker assisted selection (MAS). Here we report a ∼10 Kb deletion affecting the gene PRUPE.6G281100, 400 Kb upstream of UDP98-412, co-segregating with the trait. This gene is a leucine-rich repeat receptor-like kinase (LRR-RLK) orthologous to the Brassinosteroid insensitive 1-associated receptor kinase 1 (BAK1) group...
July 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28723952/evidence-for-prehistoric-origins-of-the-g2019s-mutation-in-the-north-african-berber-population
#9
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
#10
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/28710561/genetic-architecture-of-wild-soybean-glycine-soja-response-to-soybean-cyst-nematode-heterodera-glycines
#11
Hengyou Zhang, Qijian Song, Joshua D Griffin, Bao-Hua Song
The soybean cyst nematode (SCN) is one of the most destructive pathogens of soybean plants worldwide. Host-plant resistance is an environmentally friendly method to mitigate SCN damage. To date, the resistant soybean cultivars harbor limited genetic variation, and some are losing resistance. Thus, a better understanding of the genetic mechanisms of the SCN resistance, as well as developing diverse resistant soybean cultivars, is urgently needed. In this study, a genome-wide association study (GWAS) was conducted using 1032 wild soybean (Glycine soja) accessions with over 42,000 single-nucleotide polymorphisms (SNPs) to understand the genetic architecture of G...
July 14, 2017: Molecular Genetics and Genomics: MGG
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
#12
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/28706532/identification-of-single-nucleotide-polymorphic-loci-associated-with-biomass-yield-under-water-deficit-in-alfalfa-medicago-sativa-l-using-genome-wide-sequencing-and-association-mapping
#13
Long-Xi Yu
Alfalfa is a worldwide grown forage crop and is important due to its high biomass production and nutritional value. However, the production of alfalfa is challenged by adverse environmental factors such as drought and other stresses. Developing drought resistance alfalfa is an important breeding target for enhancing alfalfa productivity in arid and semi-arid regions. In the present study, we used genotyping-by-sequencing and genome-wide association to identify marker loci associated with biomass yield under drought in the field in a panel of diverse germplasm of alfalfa...
2017: Frontiers in Plant Science
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
#14
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
#15
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
#16
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/28691210/e3-ligase-saul1-serves-as-a-positive-regulator-of-pamp-triggered-immunity-and-its-homeostasis-is-monitored-by-immune-receptor-soc3
#17
Meixuezi Tong, Tanja Kotur, Wanwan Liang, Katja Vogelmann, Tatjana Kleine, Dario Leister, Catharina Brieske, Shuhua Yang, Daniel Lüdke, Marcel Wiermer, Yuelin Zhang, Xin Li, Stefan Hoth
In both plants and animals, intracellular nucleotide-binding leucine-rich repeat proteins (NLRs; or Nod-like receptors) serve as immune receptors to recognize pathogen-derived molecules and mount effective immune responses against microbial infections. Plant NLRs often guard the presence or activity of other host proteins, which are the direct virulence targets of pathogen effectors. These guardees are sometimes immune-promoting components such as those in a mitogen-activated protein kinase cascade. Plant E3 ligases serve many roles in immune regulation, but it is unclear whether they can also be guarded by NLRs...
September 2017: New Phytologist
https://www.readbyqxmd.com/read/28688273/leucine-rich-repeat-kinase-2-lrrk2-inhibitors-based-on-indolinone-scaffold-potential-pro-neurogenic-agents
#18
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
#19
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
https://www.readbyqxmd.com/read/28649619/variable-frequency-of-lrrk2-variants-in-the-latin-american-research-consortium-on-the-genetics-of-parkinson-s-disease-large-pd-a-case-of-ancestry
#20
Mario Cornejo-Olivas, Luis Torres, Mario R Velit-Salazar, Miguel Inca-Martinez, Pilar Mazzetti, Carlos Cosentino, Federico Micheli, Claudia Perandones, Elena Dieguez, Victor Raggio, Vitor Tumas, Vanderci Borges, Henrique B Ferraz, Carlos R M Rieder, Artur Shumacher-Schuh, Carlos Velez-Pardo, Marlene Jimenez-Del-Rio, Francisco Lopera, Jorge Chang-Castello, Brennie Andreé-Munoz, Sarah Waldherr, Dora Yearout, Cyrus P Zabetian, Ignacio F Mata
Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2), primarily located in codons G2019 and R1441, represent the most common genetic cause of Parkinson's disease in European-derived populations. However, little is known about the frequency of these mutations in Latin American populations. In addition, a prior study suggested that a LRRK2 polymorphism (p.Q1111H) specific to Latino and Amerindian populations might be a risk factor for Parkinson's disease, but this finding requires replication. We screened 1734 Parkinson's disease patients and 1097 controls enrolled in the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE-PD), which includes sites in Argentina, Brazil, Colombia, Ecuador, Peru, and Uruguay...
2017: NPJ Parkinson's Disease
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