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Leucine repeat rich kinase 2

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https://www.readbyqxmd.com/read/27920157/two-serk-receptor-like-kinases-interact-with-the-receptor-like-kinase-ems1-in-anther-cell-fate-determination
#1
Zhiyong Li, Yao Wang, Jian Huang, Nagib Ahsan, Gabriel Biener, Joel Paprocki, Jay J Thelen, Valerica Raicu, Dazhong Zhao
Cell signaling pathways mediated by leucine-rich repeat receptor-like kinases (LRR-RLK) are essential for plant growth, development and defense. The EMS1 (EXCESS MICROSPOROCYTES1) LRR-RLK and its small protein ligand TPD1 (TAPETUM DETERMINANT1) play a fundamental role in somatic and reproductive cell differentiation during early anther development in Arabidopsis (Arabidopsis thaliana). However, it is unclear whether other cell surface molecules serve as co-regulators of EMS1. Here, we show that SERK1 (SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE1) and SERK2 LRR-RLKs act redundantly as co-regulatory and physical partners of EMS1...
December 5, 2016: Plant Physiology
https://www.readbyqxmd.com/read/27913672/first-model-of-dimeric-lrrk2-the-challenge-of-unrevealing-the-structure-of-a-multidomain-parkinson-s-associated-protein
#2
REVIEW
Giambattista Guaitoli, Bernd K Gilsbach, Francesco Raimondi, Christian Johannes Gloeckner
Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common cause of Mendelian forms of Parkinson's disease, among autosomal dominant cases. Its gene product, LRRK2, is a large multidomain protein that belongs to the Roco protein family exhibiting GTPase and kinase activity, with the latter activity increased by pathogenic mutations. To allow rational drug design against LRRK2 and to understand the cross-regulation of the G- and the kinase domain at a molecular level, it is key to solve the three-dimensional structure of the protein...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913671/l-rrk-de-triomphe-a-solution-for-lrrk2-gtpase-activity
#3
REVIEW
Jonathon Nixon-Abell, Daniel C Berwick, Kirsten Harvey
Leucine-rich repeat kinase 2 (LRRK2) is a central protein in the pathogenesis of Parkinson's disease (PD), yet its normal function has proved stubbornly hard to elucidate. Even though it remains unclear how pathogenic mutations affect LRRK2 to cause PD, recent findings provide increasing cause for optimism. We summarise here the developing consensus over the effect of pathogenic mutations in the Ras of complex proteins and C-terminal of Roc domains on LRRK2 GTPase activity. This body of work has been greatly reinforced by our own study of the protective R1398H variant contained within the LRRK2 GTPase domain...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913670/screening-for-chemical-modulators-for-lrrk2
#4
REVIEW
Heather Mortiboys
After the discovery of leucine-rich repeat kinase 2 (LRRK2) as a risk factor for sporadic Parkinson's disease (PD) and mutations in LRRK2 as a cause of some forms of familial PD, there has been substantial interest in finding chemical modulators of LRRK2 function. Most of the pathogenic mutations in LRRK2 are within the enzymatic cores of the protein; therefore, many screens have focused on finding chemical modulators of this enzymatic activity. There are alternative screening approaches that could be taken to investigate compounds that modulate LRRK2 cellular functions...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913669/the-unconventional-g-protein-cycle-of-lrrk2-and-roco-proteins
#5
REVIEW
Susanne Terheyden, Laura M Nederveen-Schippers, Arjan Kortholt
Mutations in the human leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of hereditary Parkinson's disease (PD). LRRK2 belongs to the Roco family of proteins, which are characterized by the presence of a Ras of complex proteins domain (Roc), a C-terminal of Roc domain (COR) and a kinase domain. Despite intensive research, much remains unknown about activity and the effect of PD-associated mutations. Recent biochemical and structural studies suggest that LRRK2 and Roco proteins are noncanonical G-proteins that do not depend on guanine nucleotide exchange factors or GTPase-activating proteins for activation...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913668/cellular-functions-of-lrrk2-implicate-vesicular-trafficking-pathways-in-parkinson-s-disease
#6
REVIEW
Mark R Cookson
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, associated with Parkinson's disease, have been shown to affect intracellular trafficking pathways in a variety of cells and organisms. An emerging theme is that LRRK2 can bind to multiple membranous structures in cells, and several recent studies have suggested that the Rab family of small GTPases might be important in controlling the recruitment of LRRK2 to specific cellular compartments. Once localized to membranes, LRRK2 then influences downstream events, evidenced by changes in the autophagy-lysosome pathway...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27911006/lrrk2-levels-and-phosphorylation-in-parkinson-s-disease-brain-and-cases-with-restricted-lewy-bodies
#7
Nicolas Dzamko, Amanda M Gysbers, Rina Bandopadhyay, Marc F Bolliger, Akiko Uchino, Ye Zhao, Masaki Takao, Sandrine Wauters, Wilma D J van de Berg, Junko Takahashi-Fujigasaki, R Jeremy Nichols, Janice L Holton, Shigeo Murayama, Glenda M Halliday
BACKGROUND: Leucine rich repeat kinase 2 (LRRK2) is a promising target for the treatment of Parkinson's disease; however, little is known about the expression of LRRK2 in human brain and if/how LRRK2 protein levels are altered in Parkinson's disease. OBJECTIVES: We measured the protein levels of LRRK2 as well as its phosphorylation on serines 910, 935, and 973 in the postmortem brain tissue of Parkinson's disease patients and aged controls with and without Lewy bodies...
December 2, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27909054/identification-of-a-substrate-selective-exosite-within-the-metalloproteinase-anthrax-lethal-factor
#8
Allison B Goldberg, Eunice Cho, Chad J Miller, Hua Jane Lou, Benjamin E Turk
The metalloproteinase anthrax lethal factor (LF) is secreted by Bacillus anthracis to promote disease virulence through disruption of host signaling pathways. LF is a highly specific protease, exclusively cleaving mitogen-activated protein kinase kinases (MKKs) and rodent NACHT leucine-rich repeat and pyrin domain containing protein 1B (NLRP1B). How LF achieves such restricted substrate specificity is not understood. Previous studies have suggested the existence of an exosite interaction between LF and MKKs that promotes cleavage efficiency and specificity...
December 1, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27903237/leucine-rich-repeat-kinase-2-lrrk2-regulates-%C3%AE-synuclein-clearance-in-microglia
#9
Tatsunori Maekawa, Toshikuni Sasaoka, Sadahiro Azuma, Takafumi Ichikawa, Heather L Melrose, Matthew J Farrer, Fumiya Obata
BACKGROUND: α-Synuclein (αSYN) has been genetically implicated in familial and sporadic Parkinson's disease (PD), and is associated with disease susceptibility, progression and pathology. Excess amounts of αSYN are toxic to neurons. In the brain, microglial αSYN clearance is closely related to neuronal survival. Leucine-rich repeat kinase 2 (LRRK2) is the one of the other genes implicated in familial and sporadic PD. While LRRK2 is known to be expressed in microglia, its true function remains to be elucidated...
November 30, 2016: BMC Neuroscience
https://www.readbyqxmd.com/read/27890708/fbxl18-targets-lrrk2-for-proteasomal-degradation-and-attenuates-cell-toxicity
#10
Xiaodong Ding, Sandeep K Barodia, Lisha Ma, Matthew S Goldberg
Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD) and LRRK2 polymorphisms are associated with increased risk for idiopathic PD. However, the molecular mechanisms by which these mutations cause PD remain uncertain. In vitro studies indicate that disease-linked mutations in LRRK2 increase LRRK2 kinase activity and LRRK2-mediated cell toxicity. Identifying LRRK2-interacting proteins and determining their effects on LRRK2 are important for understanding LRRK2 function and for delineating the pathophysiological mechanisms of LRRK2 mutations...
November 24, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27884160/the-d-domain-of-lrrc4-anchors-erk1-2-in-the-cytoplasm-and-competitively-inhibits-mek-erk-activation-in-glioma-cells
#11
Zeyou Wang, Qin Guo, Rong Wang, Gang Xu, Peiyao Li, Yingnan Sun, Xiaoling She, Qiang Liu, Qiong Chen, Zhibin Yu, Changhong Liu, Jing Xiong, Guiyuan Li, Minghua Wu
BACKGROUND: As a well-characterized key player in various signal transduction networks, extracellular-signal-regulated kinase (ERK1/2) has been widely implicated in the development of many malignancies. We previously found that Leucine-rich repeat containing 4 (LRRC4) was a tumor suppressor and a negative regulator of the ERK/MAPK pathway in glioma tumorigenesis. However, the precise molecular role of LRRC4 in ERK signal transmission is unclear. METHODS: The interaction between LRRC4 and ERK1/2 was assessed by co-immunoprecipitation and GST pull-down assays in vivo and in vitro...
November 25, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27872856/altered-expression-of-epo-might-underlie-hepatic-hemangiomas-in-lrrk2-knockout-mice
#12
Ben Wu, Kaifu Xiao, Zhuohua Zhang, Long Ma
Parkinson's disease (PD) is a severe neurodegenerative disorder caused by progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. The molecular mechanism of PD pathogenesis is unclear. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common genetic cause of familial and sporadic PD. However, studies on LRRK2 mutant mice revealed no visible dopaminergic neuronal loss in the midbrain. While surveying a LRRK2 knockout mouse strain, we found that old animals developed age-dependent hepatic vascular growths similar to cavernous hemangiomas...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27863501/mutations-in-lrrk2-impair-nf-%C3%AE%C2%BAb-pathway-in-ipsc-derived-neurons
#13
Rakel López de Maturana, Valérie Lang, Amaia Zubiarrain, Amaya Sousa, Nerea Vázquez, Ana Gorostidi, Julio Águila, Adolfo López de Munain, Manuel Rodríguez, Rosario Sánchez-Pernaute
BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both familial and idiopathic forms of Parkinson's disease (PD). Neuroinflammation is a key event in neurodegeneration and aging, and there is mounting evidence of LRRK2 involvement in inflammatory pathways. In a previous study, we described an alteration of the inflammatory response in dermal fibroblasts from PD patients expressing the G2019S and R1441G mutations in LRRK2. METHODS: Taking advantage of cellular reprogramming, we generated induced pluripotent stem cell (iPSC) lines and neurons thereafter, harboring LRRK2(G2019S) and LRRK2(R1441G) mutations...
November 18, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27812199/leucine-rich-repeat-kinase-2-influences-fate-decision-of-human-monocytes-differentiated-from-induced-pluripotent-stem-cells
#14
Anna Speidel, Sandra Felk, Peter Reinhardt, Jared Sterneckert, Frank Gillardon
Mutations in Leucine-rich repeat kinase 2 (LRRK2) are strongly associated with familial Parkinson's disease (PD). High expression levels in immune cells suggest a role of LRRK2 in regulating the immune system. In this study, we investigated the effect of the LRRK2 (G2019S) mutation in monocytes, using a human stem cell-derived model expressing LRRK2 at endogenous levels. We discovered alterations in the differentiation pattern of LRRK2 mutant, compared to non-mutant isogenic controls, leading to accelerated monocyte production and a reduction in the non-classical CD14+CD16+ monocyte subpopulation in the LRRK2 mutant cells...
2016: PloS One
https://www.readbyqxmd.com/read/27812003/association-of-lrrk2-r1628p-variant-with-parkinson-s-disease-in-ethnic-han-chinese-and-subgroup-population
#15
Pei Zhang, Qingzhi Wang, Fengjuan Jiao, Jianguo Yan, Lijun Chen, Feng He, Qian Zhang, Bo Tian
Recent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2) gene with Parkinson's disease (PD). The R1628P variant of LRRK2 may be a specific risk factor for PD in ethnic Han-Chinese populations. This study is to elucidate the epidemiological feature of R1628P in ethnic Han-Chinese population with PD. A comprehensive meta-analysis was performed to evaluate the precise association between R1628P variant and the risk for PD in ethnic Han-Chinese and subgroups stratified by gender, onset age, or family history...
November 4, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27806688/rgaugury-a-pipeline-for-genome-wide-prediction-of-resistance-gene-analogs-rgas-in-plants
#16
Pingchuan Li, Xiande Quan, Gaofeng Jia, Jin Xiao, Sylvie Cloutier, Frank M You
BACKGROUND: Resistance gene analogs (RGAs), such as NBS-encoding proteins, receptor-like protein kinases (RLKs) and receptor-like proteins (RLPs), are potential R-genes that contain specific conserved domains and motifs. Thus, RGAs can be predicted based on their conserved structural features using bioinformatics tools. Computer programs have been developed for the identification of individual domains and motifs from the protein sequences of RGAs but none offer a systematic assessment of the different types of RGAs...
November 2, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27799832/lrrk2-inhibitors-and-their-potential-in-the-treatment-of-parkinson-s-disease-current-perspectives
#17
REVIEW
Farzaneh Atashrazm, Nicolas Dzamko
Major advances in understanding how genetics underlies Parkinson's disease (PD) have provided new opportunities for understanding disease pathogenesis and potential new targets for therapeutic intervention. One such target is leucine-rich repeat kinase 2 (LRRK2), an enigmatic enzyme implicated in both familial and idiopathic PD risk. Both academia and industry have promoted the development of potent and selective inhibitors of LRRK2, and these are currently being employed to assess the safety and efficacy of such compounds in preclinical models of PD...
2016: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/27798112/leucine-rich-repeat-kinase-2-exacerbates-neuronal-cytotoxicity-through-phosphorylation-of-histone-deacetylase3-and-histone-deacetylation
#18
Kyung Ah Han, Wongi Seol, Hyemyung Seo, CheMyong Ko, Kwang Chul Chung
Parkinson's disease (PD) is characterized by slow, progressive degeneration of dopaminergic neurons in the substantia nigra. The cause of neuronal death in PD is largely unknown, but several genetic loci, including leucine-rich repeat kinase 2 (LRRK2), have been identified. LRRK2 has guanosine triphosphatase (GTPase) and kinase activities, and mutations in LRRK2 are the major cause of autosomal-dominant familial PD. Histone deacetylases (HDACs) remove acetyl groups from lysine residues on histone tails, promoting transcriptional repression via condensation of chromatin...
October 25, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27794539/human-r1441c-lrrk2-regulates-the-synaptic-vesicle-proteome-and-phosphoproteome-in-a-drosophila-model-of-parkinson-s-disease
#19
Shariful Islam, Hendrik Nolte, Wright Jacob, Anna B Ziegler, Stefanie Pütz, Yael Grosjean, Karolina Szczepanowska, Aleksandra Trifunovic, Thomas Braun, Hermann Heumann, Rolf Heumann, Bernhard Hovemann, Darren J Moore, Marcus Krüger
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset, autosomal dominant familial Parkinson's disease (PD) and variation at the LRRK2 locus contributes to the risk for idiopathic PD. LRRK2 can function as a protein kinase and mutations lead to increased kinase activity. To elucidate the pathophysiological mechanism of the R1441C mutation in the GTPase domain of LRRK2, we expressed human wild-type or R1441C LRRK2 in dopaminergic neurons of Drosophila and observe reduced locomotor activity, impaired survival and an age-dependent degeneration of dopaminergic neurons thereby creating a new PD-like model...
October 29, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27790061/lrrk2-inhibits-fak-activity-by-promoting-ferm-mediated-autoinhibition-of-fak-and-recruiting-the-tyrosine-phosphatase-shp-2
#20
Insup Choi, Ji-Won Byun, Sang Myun Park, Ilo Jou, Eun-Hye Joe
Mutation of leucine-rich repeat kinase 2 (LRRK2) causes an autosomal dominant and late-onset familial Parkinson's disease (PD). Recently, we reported that LRRK2 directly binds to and phosphorylates the threonine 474 (T474)-containing Thr-X-Arg(Lys) (TXR) motif of focal adhesion kinase (FAK), thereby inhibiting the phosphorylation of FAK at tyrosine (Y) 397 residue (pY397-FAK), which is a marker of its activation. Mechanistically, however, it remained unclear how T474-FAK phosphorylation suppressed FAK activation...
October 2016: Experimental Neurobiology
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