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https://www.readbyqxmd.com/read/28941828/fatigue-correlates-with-lrrk2-g2385r-variant-in-chinese-parkinson-s-disease-patients
#1
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/28930069/initial-elevations-in-glutamate-and-dopamine-neurotransmission-decline-with-age-as-does-exploratory-behavior-in-lrrk2-g2019s-knock-in-mice
#2
Mattia Volta, Dayne A Beccano-Kelly, Sarah A Paschall, Stefano Cataldi, Sarah E MacIsaac, Naila Kuhlmann, Chelsie A Kadgien, Igor Tatarnikov, Jesse Fox, Jaskaran Khinda, Emma Mitchell, Sabrina Bergeron, Heather Melrose, Matthew J Farrer, Austen J Milnerwood
LRRK2 mutations produce end-stage Parkinson's disease (PD) with reduced nigrostriatal dopamine. Conversely, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across ages. Young GKI exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses...
September 20, 2017: ELife
https://www.readbyqxmd.com/read/28918051/lrrk2-antisense-oligonucleotides-ameliorate-%C3%AE-synuclein-inclusion-formation-in-a-parkinson-s-disease-mouse-model
#3
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/28893563/the-impact-of-murine-lrrk2-g2019s-transgene-overexpression-on-acute-responses-to-inflammatory-challenge
#4
Darcy Litteljohn, Chris Rudyk, Zach Dwyer, Kyle Farmer, Teresa Fortin, Shawn Hayley
The most common Parkinson's disease (PD) mutation is the gain-of-function LRRK2 G2019S variant, which has also been linked to inflammatory disease states. Yet, little is known of the role of G2019S in PD related complex behavioral or immune/hormonal processes in response to inflammatory/toxicant challenges. Hence, we characterized the behavioural, neuroendocrine-immune and central monoaminergic responses in G2019S overexpressing mutants following systemic interferon-gamma (IFN-γ) or lipopolysaccharide (LPS) administration...
September 8, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28890071/serum-lipid-alterations-in-gba-associated-parkinson-s-disease
#5
Leonor Correia Guedes, Robin Barry Chan, Marcos António Gomes, Vasco A Conceição, Raquel Bouça Machado, Tiago Soares, Yimeng Xu, Paulo Gaspar, Joao André Carriço, Roy N Alcalay, Joaquim J Ferreira, Tiago Fleming Outeiro, Gabriel Miltenberger-Miltenyi
INTRODUCTION: Mutations in the GBA gene, encoding for the lysosomal enzyme glucocerebrosidase, are associated with Gaucher disease. Alterations in plasma sphingolipids have been reported in Gaucher, and similarly in brain extracts in Lewy body disease. As GBA mutations are prevalent risk factors for Parkinson's disease and overlap of molecular pathways are presumable, here we assessed the lipid profiles in Parkinson's patients with and without GBA mutations. METHODS: We sequenced all GBA exons in 415 Parkinson's patients, previously genotyped for LRRK2...
September 1, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28888991/lrrk2-functions-as-a-scaffolding-kinase-of-ask1-mediated-neuronal-cell-death
#6
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/28876231/the-lrr-roc-cor-module-of-the-chlorobium-tepidum-roco-protein-crystallization-and-x-ray-crystallographic-analysis
#7
Egon Deyaert, Arjan Kortholt, Wim Versées
Roco proteins are characterized by the presence of a Roc-COR supradomain harbouring GTPase activity, which is often preceded by an LRR domain. The most notorious member of the Roco protein family is the Parkinson's disease-associated LRRK2. The Roco protein from the bacterium Chlorobium tepidum has been used as a model system to investigate the structure and mechanism of this class of enzymes. Here, the crystallization and crystallographic analysis of the LRR-Roc-COR construct of the C. tepidum Roco protein is reported...
September 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/28867149/establishing-the-role-of-rare-coding-variants-in-known-parkinson-s-disease-risk-loci
#8
Iris E Jansen, J Raphael Gibbs, Mike A Nalls, T Ryan Price, Steven Lubbe, Jeroen van Rooij, André G Uitterlinden, Robert Kraaij, Nigel M Williams, Alexis Brice, John Hardy, Nicholas W Wood, Huw R Morris, Thomas Gasser, Andrew B Singleton, Peter Heutink, Manu Sharma
Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities...
November 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28864907/alterations-in-the-reduced-pteridine-contents-in-the-cerebrospinal-fluids-of-lrrk2-mutation-carriers-and-patients-with-parkinson-s-disease
#9
Hiroshi Ichinose, Ken-Ichi Inoue, Shinobu Arakawa, Yuki Watanabe, Hiroki Kurosaki, Shoko Koshiba, Eldbjorg Hustad, Masahiko Takada, Jan O Aasly
Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase that is essential for the biosynthesis of dopamine. Parkinson's disease (PD) is characterized by a progressive degeneration of nigrostriatal dopaminergic neurons, and biomarkers reflecting the degree of neurodegeneration are important not only for basic research but also for clinical diagnosis and the treatment of the disease. Although the total neopterin and biopterin levels in the cerebrospinal fluids (CSF) of the patients with PD were reported, alterations in the composition of reduced and oxidized forms of pteridine compounds have not been examined...
September 1, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28860483/selective-lrrk2-kinase-inhibition-reduces-phosphorylation-of-endogenous-rab10-and-rab12-in-human-peripheral-mononuclear-blood-cells
#10
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/28848400/af-6-protects-against-dopaminergic-dysfunction-and-mitochondrial-abnormalities-in-drosophila-models-of-parkinson-s-disease
#11
Adeline H Basil, Joan P L Sim, Grace G Y Lim, Shuping Lin, Hui Ying Chan, Simone Engelender, Kah-Leong Lim
Afadin 6 (AF-6) is an F-actin binding multidomain-containing scaffolding protein that is known for its function in cell-cell adhesion. Interestingly, besides this well documented role, we recently found that AF-6 is a Parkin-interacting protein that augments Parkin/PINK1-mediated mitophagy. Notably, mutations in Parkin and PINK1 are causative of recessively inherited forms of Parkinson's disease (PD) and aberrant mitochondrial homeostasis is thought to underlie PD pathogenesis. Given the novel role of AF-6 in mitochondrial quality control (QC), we hypothesized that AF-6 overexpression may be beneficial to PD...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28821568/lrrk2-promotes-the-activation-of-nlrc4-inflammasome-during-salmonella-typhimurium-infection
#12
Weiwei Liu, Xia'nan Liu, Yu Li, Junjie Zhao, Zhenshan Liu, Zhuqin Hu, Ying Wang, Yufeng Yao, Aaron W Miller, Bing Su, Mark R Cookson, Xiaoxia Li, Zizhen Kang
Although genetic polymorphisms in the LRRK2 gene are associated with a variety of diseases, the physiological function of LRRK2 remains poorly understood. In this study, we report a crucial role for LRRK2 in the activation of the NLRC4 inflammasome during host defense against Salmonella enteric serovar Typhimurium infection. LRRK2 deficiency reduced caspase-1 activation and IL-1β secretion in response to NLRC4 inflammasome activators in macrophages. Lrrk2(-/-) mice exhibited impaired clearance of pathogens after acute S...
August 18, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28819229/cryo-em-analysis-of-homodimeric-full-length-lrrk2-and-lrrk1-protein-complexes
#13
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/28816057/mitochondrial-complex-i-reversible-s-nitrosation-improves-bioenergetics-and-is-protective-in-parkinson-s-disease
#14
Chiara Milanese, Victor Tapias, Sylvia Gabriels, Silvia Cerri, Giovanna Levandis, Fabio Blandini, Maria Tresini, Sruti Shiva, John Timothy Greenamyre, Mark T Gladwin, Pier G Mastroberardino
AIMS: This study was designed to explore the neuroprotective potential of inorganic nitrite as a new therapeutic avenue in Parkinson's disease (PD). RESULTS: Administration of inorganic nitrite ameliorates neuropathology in phylogenetically distinct animal models of PD. Beneficial effects are not confined to prophylactic treatment and also occur if nitrite is administered when the pathogenic cascade is already active. Mechanistically, the effect is mediated by both complex I S-nitrosation, which under nitrite administration is favored over formation of other forms of oxidation, and down-stream activation of the antioxidant Nrf2 pathway...
September 21, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28802919/nonmotor-signs-in-genetic-forms-of-parkinson-s-disease
#15
Meike Kasten, Connie Marras, Christine Klein
Although only a minority (i.e., ~5%) of Parkinson's disease (PD) cases is due to well-defined genetic causes, important clues about the common, "idiopathic" PD (iPD) can be garnered from monogenic model diseases. Nonmotor signs (NMS) are also present in monogenic PD and reviewed in this chapter for the confirmed PD genes SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and the risk factor gene GBA. Within the context of the MDSGene database (www.mdsgene.org), we performed a systematic literature search and extracted information on cognitive decline, depression, psychotic signs and symptoms, autonomic signs and symptoms, anxiety, sleep disorder, and olfactory impairment...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28802631/the-design-and-sar-of-a-novel-series-of-2-aminopyridine-based-lrrk2-inhibitors
#16
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
#17
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/28768533/progression-of-pathology-in-pink1-deficient-mouse-brain-from-splicing-via-ubiquitination-er-stress-and-mitophagy-changes-to-neuroinflammation
#18
Sylvia Torres-Odio, Jana Key, Hans-Hermann Hoepken, Júlia Canet-Pons, Lucie Valek, Bastian Roller, Michael Walter, Blas Morales-Gordo, David Meierhofer, Patrick N Harter, Michel Mittelbronn, Irmgard Tegeder, Suzana Gispert, Georg Auburger
BACKGROUND: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson's disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types. METHODS: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms...
August 2, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28764903/achieving-neuroprotection-with-lrrk2-kinase-inhibitors-in-parkinson-disease
#19
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/28751472/parkinson-disease-associated-lrrk2-g2019s-transgene-disrupts-marrow-myelopoiesis-and-peripheral-th17-response
#20
Jeongho Park, Jang-Won Lee, Scott C Cooper, Hal E Broxmeyer, Jason R Cannon, Chang H Kim
Parkinson's disease (PD) is a neurodegenerative disease, whereas Crohn's disease is an inflammatory bowel disease. Interestingly, polymorphisms in the LRRK2 gene have been identified as risk factors for both diseases. LRRK2 G2019S is the most prevalent mutation found in PD. To gain insights into the role of the LRRK2 G2019S gene on the development and activation of the immune system in the brain-gut axis, we investigated the effect of LRRK2 G2019S on bone marrow myeloid progenitors and myeloid cell function in the periphery...
July 27, 2017: Journal of Leukocyte Biology
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