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Leucine rich repeate kinase

Claudia Manzoni, Adamantios Mamais, Sybille Dihanich, Marc P M Soutar, Helene Plun-Favreau, Rina Bandopadhyay, Rosella Abeti, Paola Giunti, John Hardy, Mark 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 this 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)...
March 21, 2018: Bioscience Reports
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...
March 16, 2018: Journal of Alzheimer's Disease: JAD
Astrid Kritzinger, Boris Ferger, Frank Gillardon, Birgit Stierstorfer, Gerald Birk, Stefan Kochanek, Thomas Ciossek
Mutations in leucine-rich repeat kinase 2 (LRRK2) age-dependently cause Parkinson's disease and are associated with several inflammatory diseases. So far, the potential role of LRRK2 expression in glial cells as mediators of neuroinflammation and the influence of aging have not been investigated in viral vector-based LRRK2 animal models. In this study, we compared the effect of striatal injection of high-capacity adenoviral vectors expressing either a kinase-overactive LRRK2 with the familial G2019S mutation or a kinase-inactive LRRK2 variant in young and old C57BL/6J mice...
February 16, 2018: Neurobiology of Aging
Hidejiro Torigoe, Hiromasa Yamamoto, Masakiyo Sakaguchi, Chen Youyi, Kei Namba, Hiroki Sato, Kazuhiko Shien, Junichi Soh, Ken Suzawa, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka
Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations, and have been targeted for treatment in non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues...
March 13, 2018: Carcinogenesis
Yue Ma, Chunquan Zheng, Le Shi
Background: Chronic rhinosinusitis (CRS), commonly divided into CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) is an inflammatory disease which mechanism remain unclear. Leucine-rich repeat kinase 2 (LRRK2) has been proved to be a negative regulator of inflammation response while its role in pathogenesis of CRS has yet to be revealed. This research study was designed to investigate the relationship between the expression level and biologic role of LRRK2 in CRS. Methods: Expression of LRRK2 mRNA and noncoding repressor of NFAT (NRON) were examined by qRT-PCR...
2018: Clinical and Translational Allergy
Qin Rui, Haibo Ni, Fan Gao, Baoqi Dang, Di Li, Rong Gao, Gang Chen
Leucine-rich repeat kinase 2 (LRRK2) is widely expressed in the brain and exerts neurotoxicity in Parkinson's disease. The p38/Drosha signaling activation has been reported to increase cell death under stress. This study was designed to investigate the potential role and mechanism of LRRK2 in secondary brain injury after traumatic brain injury (TBI). A total of 130 male Sprague-Dawley rats were examined using a weight-drop model of TBI. The rats received the specific LRRK2 inhibitor PF-06447475 or LRRK2 pDNA alone or in combination with Drosha pDNA...
2018: Frontiers in Cellular Neuroscience
Byoung Il Je, Fang Xu, Qingyu Wu, Lei Liu, Robert Meeley, Joseph P Gallagher, Leo Corcilius, Richard J Payne, Madelaine E Bartlett, David Jackson
Meristems contain groups of indeterminate stem cells, which are maintained by a feedback loop between CLAVATA ( CLV ) and WUSCHEL ( WUS ) signaling. CLV signaling involves the secretion of the CLV3 peptide and its perception by a number of Leucine-Rich-Repeat (LRR) receptors, including the receptor-like kinase CLV1 and the receptor-like protein CLV2 coupled with the CORYNE (CRN) pseudokinase. CLV2, and its maize ortholog FASCIATED EAR2 (FEA2) appear to function in signaling by CLV3 and several related CLV3/EMBRYO-SURROUNDING REGION (CLE) peptide ligands...
March 15, 2018: ELife
Maria Perez Carrion, Francesca Pischedda, Alice Biosa, Isabella Russo, Letizia Straniero, Laura Civiero, Marianna Guida, Christian J Gloeckner, Nicola Ticozzi, Cinzia Tiloca, Claudio Mariani, Gianni Pezzoli, Stefano Duga, Irene Pichler, Lifeng Pan, John E Landers, Elisa Greggio, Michael W Hess, Stefano Goldwurm, Giovanni Piccoli
Mutations in leucine-rich repeat kinase 2 gene ( LRRK2 ) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains, including 13 putative armadillo-type repeats at the N-terminus. In this study, we analyzed the functional and molecular consequences of a novel variant, E193K, identified in an Italian family. E193K substitution does not influence LRRK2 kinase activity. Instead it affects LRRK2 biochemical properties, such as phosphorylation at Ser935 and affinity for 14-3-3ε...
2018: Frontiers in Molecular Neuroscience
Panagiotis S Athanasopoulos, Rolf Heumann, Arjan Kortholt
Mutations in human leucine-rich-repeat kinase 2 (LRRK2) have been found to be the most frequent cause of late-onset Parkinson's Disease (PD). LRRK2 is a large protein with two enzymatic domains, a GTPase and a kinase domain. A cluster of (auto)-phosphorylation sites within the N-terminus of LRRK2 have been shown to be crucial for the localization of LRRK2 and is important for PD pathogenesis. In addition, phosphorylation of sites within the G-domain of the protein affect GTPase activity. Here we discuss the role of these (auto)-phosphorylation sites of LRRK2 and their regulation by phosphatases and upstream kinases...
March 12, 2018: Biological Chemistry
Ulrich Hohmann, Julia Santiago, Joël Nicolet, Vilde Olsson, Fabio M Spiga, Ludwig A Hothorn, Melinka A Butenko, Michael Hothorn
Plant-unique membrane receptor kinases with leucine-rich repeat ectodomains (LRR-RKs) can sense small molecule, peptide, and protein ligands. Many LRR-RKs require SERK-family coreceptor kinases for high-affinity ligand binding and receptor activation. How one coreceptor can contribute to the specific binding of distinct ligands and activation of different LRR-RKs is poorly understood. Here we quantitatively analyze the contribution of SERK3 to ligand binding and activation of the brassinosteroid receptor BRI1 and the peptide hormone receptor HAESA...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Alexia F Kalogeropulou, Jing Zhao, Marc F Bolliger, Anna Memou, Shreya Narasimha, Tyler P Molitor, William H Wilson, Hardy J Rideout, R Jeremy Nichols
Autosomal dominant, missense mutations in the Leucine Rich Repeat protein Kinase 2 ( LRRK2 ) gene are the most common genetic predisposition to develop Parkinson's disease (PD). LRRK2 kinase activity is increased in several pathogenic mutations [N1437H, R1441C/G/H, Y1699C, G2019S], implicating hyperphosphorylation of a substrate in the pathogenesis of disease. Identification of the downstream targets of LRRK2 is a crucial endeavor in the field to understand LRRK2 pathway dysfunction in disease. We have identified the signaling adapter protein p62/SQSTM1 as a novel endogenous interacting partner and substrate of LRRK2...
March 8, 2018: Biochemical Journal
Qin Chen, Xiaoyan Huang, Renjie Li
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), as a long chain non-coding RNA (lncRNA), has been reported to be upregulated in Parkinson's disease (PD). However, the mechanisms underlying this process remain unknown. Hence, to investigate the role of MALAT1 in PD, N-methyl-4-phenylpyridinium (MPP+ ) was used to induce PD in vitro in the MN9D dopaminergic neuronal cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to induce PD in vivo in C57BL/6 mice. Quantitative Real-Time PCR (qRT-PCR) and western blot assay showed that the expression levels of MALAT1 and leucine-rich repeat kinase (LRRK2) were increased, and that of miR-205-5p was decreased in the midbrains of mice in which PD was induced by MPTP...
2018: American Journal of Translational Research
Qian Wang, Furao Liu, Meichao Zhang, Pingting Zhou, Ci Xu, Yanyan Li, Lei Bian, Yuanhua Liu, Yuan Yao, Fei Wang, Yong Fang, Dong Li
Neutrophils are the most important component of the innate immune system. Mechanistic understanding of the mechanism underlying neutrophil differentiation remains elusive. Using genome-wide RNA-seq, we identified genes whose expression is dramatically up-regulated during neutrophil differentiation. Among them is nucleotide-binding leucine-rich repeat and pyrindomain-containing receptor 12 (NLRP12), which plays a role in immune inflammatory responses. Genetic ablation of NLRP12 suppresses NF-κB inducing kinase (NIK) stabilization, RelB nuclear translocation and neutrophil differentiation in vitro...
2018: International Journal of Biological Sciences
Miao Yu, Muhammad Arshad, Wenmin Wang, Dongyu Zhao, Li Xu, Linkang Zhou
BACKGROUND: Several mutations in leucine rich repeat kinase 2 (LRRK2) gene have been associated with pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder marked by resting tremors, and rigidity, leading to Postural instability. It has been revealed that mutations that lead to an increase of kinase activity of LRRK2 protein are significantly associated with PD pathogenesis. Recent studies have shown that some Rab GTPases, especially Rab8, serve as substrates of LRRK2 and undergo phosphorylation in its switch II domain upon interaction...
February 27, 2018: Lipids in Health and Disease
Kelsey Lee, Khanh-Dung Nguyen, Chao Sun, Mei Liu, Faria Zafar, Jimmy Saetern, Adrian Flierl, James W Tetrud, J William Langston, Dennis Dickson, Birgitt Schüle
BACKGROUND: Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are among the most common genetic causes of Lewy body Parkinson's disease (PD). However, LRRK2 mutations can also lead to a variety of pathological phenotypes other than typical PD, including relatively pure nigrostriatal cell loss without alpha-synuclein-positive Lewy bodies or Lewy neurites, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). The mechanisms behind this remarkable pleomorphic pathology are currently unclear...
2018: Journal of Parkinson's Disease
Rubén Fernández-Santiago, Alicia Garrido, Jon Infante, Isabel González-Aramburu, María Sierra, Manel Fernández, Francesc Valldeoriola, Esteban Muñoz, Yaroslau Compta, María-José Martí, José Ríos, Eduardo Tolosa, Mario Ezquerra
OBJECTIVES: A recent study showed that Arab-Berbers GG homozygous at rs2421947(C/G) in the dynamin 3 gene (DNM3) had 12.5 years earlier age at onset of leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD) (L2PD). We explored whether this variant modulates the L2PD age at onset in Spain. METHODS: We genotyped rs2421947 in 329 participants (210 L2PD patients, 119 L2PD nonmanifesting p.G2019S carriers), and marker rs356219 (A/G) in the α-synuclein gene (SNCA)...
February 23, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
Qin Rui, Haibo Ni, Di Li, Rong Gao, Gang Chen
The leucine-rich repeat kinase 2 (LRRK2) gene and α-synuclein gene (SNCA) are the key influence factors of Parkinson's disease (PD). It is reported that dysfunction of LRRK2 may influence the accumulation of α-synuclein and its pathology to alter cellular functions and signaling pathways by the kinase activation of LRRK2. The accumulation of α-synuclein is one of the main stimulants of microglias acitiviton. Microglias are macrophages resided in the brain, and activation of microglials is believed to contribute to neuroinflammation and neuronal death in PD...
February 22, 2018: Current Neuropharmacology
Alicia Yoke Wei Wong, Vasilis Oikonomou, Giuseppe Paolicelli, Antonella De Luca, Marilena Pariano, Jan Fric, Hock Soon Tay, Paola Ricciardi-Castagnoli, Teresa Zelante
The Parkinson's disease-associated protein, Leucine-rich repeat kinase 2 (LRRK2), a known negative regulator of nuclear factor of activated T cells (NFAT), is expressed in myeloid cells such as macrophages and dendritic cells (DCs) and is involved in the host immune response against pathogens. Since, the Ca2+ /NFAT/IL-2 axis has been previously found to regulate DC response to the fungus Aspergillus , we have investigated the role played by the kinase LRRK2 during fungal infection. Mechanistically, we found that in the early stages of the non-canonical autophagic response of DCs to the germinated spores of Aspergillus , LRRK2 undergoes progressive degradation and regulates NFAT translocation from the cytoplasm to the nucleus...
2018: Frontiers in Immunology
Nasia Antoniou, Dimitrios Vlachakis, Anna Memou, Emmanouela Leandrou, Polytimi-Eleni Valkimadi, Katerina Melachroinou, Diane B Re, Serge Przedborski, William T Dauer, Leonidas Stefanis, Hardy J Rideout
In experimental models, both in vivo and cellular, over-expression of Parkinson's linked mutant leucine-rich repeat kinase 2 (LRRK2) is sufficient to induce neuronal death. While several cell death associated proteins have been linked to LRRK2, either as protein interactors or as putative substrates, characterization of the neuronal death cascade remains elusive. In this study, we have mapped for the first time the domain within LRRK2 that mediates the interaction with FADD, thereby activating the molecular machinery of the extrinsic death pathway...
February 22, 2018: Scientific Reports
Ning Yuan, Shuangrong Yuan, Zhigang Li, Man Zhou, Peipei Wu, Qian Hu, Liangjiang Wang, Venugopal Mendu, Hong Luo
Protein kinases play fundamental roles in plant development and environmental stress responses. Here, we identified the STRESS INDUCED FACTOR (SIF) gene family, which encodes four leucine-rich repeat receptor-like protein kinases (LRR-RLKs) in Arabidopsis thaliana. The four genes, SIF1-4, are clustered in the genome and highly conserved, but have temporally and spatially distinct expression patterns. We employed Arabidopsis SIF knockout mutants and overexpression transgenics to examine SIF involvement during plant pathogen defense...
February 20, 2018: Plant Physiology
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