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https://www.readbyqxmd.com/read/28330897/rip2-is-required-for-nod2-mediated-lysozyme-sorting-in-paneth-cells
#1
Haifang Wang, Xinwen Zhang, Zhanguang Zuo, Qin Zhang, Ying Pan, Benhua Zeng, Wenxia Li, Hong Wei, Zhihua Liu
Paneth cells play an important role in maintaining intestinal homeostasis by secreting a large number of antimicrobial peptides into the intestinal lumen. In this study, we found that Rip2 is required for lysozyme sorting in Paneth cells in a manner that is dependent on Nod2, LRRK2, and Rab2a. Rip2 deficiency in mouse led to lysosomal degradation of lysozyme in Paneth cells and prevented the recruitment of Rab2a onto dense core vesicles (DCVs). Like Nod2 and LRRK2, Rip2 localizes to DCVs in Paneth cells, and its DCV localization depends on Nod2 and LRRK2...
March 22, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28321439/overexpression-of-parkinson-s-disease-associated-mutation-lrrk2-g2019s-in-mouse-forebrain-induces-behavioral-deficits-and-%C3%AE-synuclein-pathology
#2
Yulan Xiong, Stewart Neifert, Senthilkumar S Karuppagounder, Jeannette N Stankowski, Byoung Dae Lee, Jonathan C Grima, Guanxing Chen, Han Seok Ko, Yunjong Lee, Debbie Swing, Lino Tessarollo, Ted M Dawson, Valina L Dawson
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an unambiguous cause of late-onset, autosomal-dominant familial Parkinson's disease (PD) and LRRK2 mutations are the strongest genetic risk factor for sporadic PD known to date. A number of transgenic mice expressing wild-type or mutant LRRK2 have been described with varying degrees of LRRK2-related abnormalities and modest pathologies. None of these studies directly addressed the role of the kinase domain in the changes observed and none of the mice present with robust features of the human disease...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28320779/the-g2385r-risk-factor-for-parkinson-s-disease-enhances-chip-dependent-intracellular-degradation-of-lrrk2
#3
Iakov N Rudenko, Alice Kaganovich, Rebekah G Langston, Aleksandra Beilina, Kelechi Ndukwe, Ravindran Kumaran, Allissa A Dillman, Ruth Chia, Mark R Cookson
Autosomal dominant mutations in leucine-rich repeat kinase 2 ( LRRK2 ) are associated with Parkinson's disease (PD). Most pathogenic LRRK2 mutations result in amino-acid substitutions in the central ROC-COR-Kinase triple domain and affect enzymatic functions of the protein. However, there are several variants in LRRK2 , including the risk factor G2385R, that impact PD pathogenesis by unknown mechanisms. Previously, we have shown that G2385R LRRK2 has decreased kinase activity in vitro and altered affinity to LRRK2 interactors...
March 20, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28314412/development-of-lrrk2-inhibitors-for-the-treatment-of-parkinson-s-disease
#4
K V Christensen, G P Smith, D S Williamson
Linkage and genome-wide association studies have identified a genetic risk locus for late-onset Parkinson's disease in chromosome 12, originally identified as PARK6. The causative gene was identified to code for a large multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). The combined genetic and biochemical evidence supports a hypothesis in which the LRRK2 kinase function is causally involved in the pathogenesis of sporadic and familial forms of PD, and therefore that LRRK2 kinase inhibitors could be useful for treatment...
2017: Progress in Medicinal Chemistry
https://www.readbyqxmd.com/read/28292328/age-dependent-dopamine-transporter-dysfunction-and-serine129-phospho-%C3%AE-synuclein-overload-in-g2019s-lrrk2-mice
#5
Francesco Longo, Daniela Mercatelli, Salvatore Novello, Ludovico Arcuri, Alberto Brugnoli, Fabrizio Vincenzi, Isabella Russo, Giulia Berti, Omar S Mabrouk, Robert T Kennedy, Derya R Shimshek, Katia Varani, Luigi Bubacco, Elisa Greggio, Michele Morari
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease. Here, we investigated whether the G2019S LRRK2 mutation causes morphological and/or functional changes at nigro-striatal dopamine neurons. Density of striatal dopaminergic terminals, nigral cell counts, tyrosine hydroxylase protein levels as well as exocytotic dopamine release measured in striatal synaptosomes, or striatal extracellular dopamine levels monitored by in vivo microdialysis were similar between ≥12-month-old G2019S knock-in mice and wild-type controls...
March 14, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28289968/synthesis-and-in-vitro-and-in-vivo-evaluation-of-3-h-lrrk2-in-1-as-a-novel-radioligand-for-lrrk2
#6
Noeen Malik, Andrew N Gifford, Johan Sandell, Daniel Tuchman, Yu-Shin Ding
PURPOSE: LRRK2 (leucine-rich repeat kinase 2) has recently been proven to be a promising drug target for Parkinson's disease (PD) due to an apparent enhanced activity caused by mutations associated with familial PD. To date, there have been no reports in which a LRRK2 inhibitor has been radiolabeled and used for in in vitro or in vivo studies of LRRK2. In the present study, we radiolabeled the LRRK2 ligand, LRRK-IN-1, for the purposes of performing in vitro (IC50, K d , B max, autoradiography) and in vivo (biodistribution, and blocking experiments) evaluations in rodents and human striatum tissues...
March 13, 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
https://www.readbyqxmd.com/read/28289797/-epidemiology-and-causes-of-parkinson-s-disease
#7
C M Lill, C Klein
Parkinson's disease (PD) is the second most common neurodegenerative disease and has a growing socioeconomic impact due to demographic changes in the industrial nations. There are several forms of PD, a fraction of which (<5%) are monogenic, i. e. caused by mutations in single genes. At present, six genes have been established for the clinically classical form of parkinsonism including three autosomal dominantly (SNCA, LRRK2, VPS35) and three autosomal recessively inherited ones (Parkin, PINK1, DJ-1)...
March 13, 2017: Der Nervenarzt
https://www.readbyqxmd.com/read/28282269/endoa-endophilin-a-creates-docking-stations-for-autophagic-proteins-at-synapses
#8
Sandra-Fausia Soukup, Patrik Verstreken
Synapses are very specialized compartments with high metabolic demand to maintain neurotransmission, an essential step for basic brain function. Neurons are post-mitotic and synapses need to stay functional over time-sometimes over decades. Given that synapses are often at a long distance from the cell body, they must use local mechanisms to regulate protein quality control. We show that macroautophagy/autophagy is one of these local processes and found that it is under strict control of the synapse-enriched protein EndoA/Endophilin-A, previously only implicated in endocytosis...
February 15, 2017: Autophagy
https://www.readbyqxmd.com/read/28280464/endogenous-leucine-rich-repeat-kinase-2-slows-synaptic-vesicle-recycling-in-striatal-neurons
#9
James W Jr Maas, Jing Yang, Robert H Edwards
Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) produce the most common inherited form of Parkinson's disease (PD) but the function of LRRK2 remains poorly understood. The presynaptic role of multiple genes linked to PD including α-synuclein (α-syn) has suggested that LRRK2 may also influence neurotransmitter release, a possibility supported by recent work. However, the use of disease-associated mutants that cause toxicity complicates the analysis. To determine whether LRRK2 normally influences the synaptic vesicle, we have now used a combination of imaging and electrophysiology to study LRRK2 knockout (KO) mice...
2017: Frontiers in Synaptic Neuroscience
https://www.readbyqxmd.com/read/28251720/prevalence-of-parkinson-s-disease-a-population-based-study-in-portugal
#10
J J Ferreira, N Gonçalves, A Valadas, C Januário, M R Silva, L Nogueira, J L M Vieira, A B Lima
BACKGROUND AND PURPOSE: Portugal has been identified as one of the countries with a high prevalence of LRRK2-G2019S, considered to be the most frequent known cause of familial and sporadic Parkinson's disease (PD). The aim of this study was to evaluate the prevalence of PD in Portugal using a door-to-door methodology. METHODS: A cross-sectional study was conducted in the Portuguese community-dwelling population; that is, elderly people living in the community on their own, aged ≥50 years and resident in mainland Portugal, in two phases: (i) a questionnaire was applied to screen potential cases of PD; and (ii) screened cases were evaluated by an expert in PD to confirm diagnosis...
March 2, 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/28245354/discovery-of-a-3-4-pyrimidinyl-indazole-mli-2-an-orally-available-and-selective-leucine-rich-repeat-kinase-2-lrrk2-inhibitor-that-reduces-brain-kinase-activity
#11
Jack D Scott, Duane E DeMong, Thomas J Greshock, Kallol Basu, Xing Dai, Joel Harris, Alan Hruza, Sarah W Li, Sue-Ing Lin, Hong Liu, Megan K Macala, Zhiyong Hu, Hong Mei, Honglu Zhang, Paul Walsh, Marc Poirier, Zhi-Cai Shi, Li Xiao, Gautam Agnihotri, Marco A S Baptista, John Columbus, Matthew J Fell, Lynn A Hyde, Reshma Kuvelkar, Yinghui Lin, Christian Mirescu, John A Morrow, Zhizhang Yin, Xiaoping Zhang, Xiaoping Zhou, Ronald K Chang, Mark W Embrey, John M Sanders, Heather E Tiscia, Robert E Drolet, Jonathan T Kern, Sylvie M Sur, John J Renger, Mark T Bilodeau, Matthew E Kennedy, Eric M Parker, Andrew W Stamford, Ravi P Nargund, John A McCauley, Michael W Miller
: Leucine-Rich Repeat Kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's Disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of effecting disesase progression, our team set out to develop LRRK2 inhibitors to test this hypothesis...
February 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28235153/distinctive-genomic-signature-of-neural-and-intestinal-organoids-from-familial-parkinson-s-disease-patient-derived-induced-pluripotent-stem-cells
#12
Mi-Young Son, Hyuna Sim, Ye Seul Son, Kwang Bo Jung, Mi-Ok Lee, Jung-Hwa Oh, Sun-Ku Chung, Cho-Rok Jung, Janghwan Kim
AIMS: The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic cause of Parkinson's disease (PD). There is compelling evidence that PD is not only a brain disease but also a gastrointestinal disorder; nonetheless, its pathogenesis remains unclear. We aimed to develop human neural and intestinal tissue models of PD patients harboring an LRRK2 mutation to understand the link between LRRK2 and PD pathology by investigating the gene expression signature. METHODS: We generated PD patient-specific induced pluripotent stem cells (iPSCs) carrying an LRRK2 G2019S mutation (LK2GS) and then differentiated into three-dimensional (3D) human neuroectodermal spheres (hNESs) and human intestinal organoids (hIOs)...
February 24, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28224253/lrrk2-expression-in-the-enteric-nervous-system-ensuring-its-significance
#13
EDITORIAL
Pascal Derkinderen
No abstract text is available yet for this article.
February 21, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/28223019/synthesis-of-11-c-hg-10-102-01-as-a-new-potential-pet-agent-for-imaging-of-lrrk2-enzyme-in-parkinson-s-disease
#14
Min Wang, Mingzhang Gao, Zhidong Xu, Qi-Huang Zheng
The reference standard (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (HG-10-102-01) and its precursor (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-hydroxyphenyl)(morpholino)methanone (desmethyl-HG-10-102-01) were synthesized from 2,4,5-trichloropyrimide and 3-methoxy-4-nitrobenzoic acid with overall chemical yield 49% in four steps and 14% in five steps, respectively. The target tracer (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-[(11)C]methoxyphenyl)(morpholino)methanone ([(11)C]HG-10-102-01) was prepared from the precursor desmethyl-HG-10-102-01 with [(11)C]CH3OTf through O-[(11)C]methylation and isolated by HPLC combined with SPE in 45-55% radiochemical yield, based on [(11)C]CO2 and decay corrected to end of bombardment (EOB)...
February 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28222538/vps35-the-retromer-complex-and-parkinson-s-disease
#15
Erin T Williams, Xi Chen, Darren J Moore
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene encoding a core component of the retromer complex, have recently emerged as a new cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, AspD620Asn (D620N), has so far been unambiguously identified to cause PD in multiple individuals and families worldwide. The exact molecular mechanism(s) by which VPS35 mutations induce progressive neurodegeneration in PD are not yet known. Understanding these mechanisms, as well as the perturbed cellular pathways downstream of mutant VPS35, is important for the development of appropriate therapeutic strategies...
February 8, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28220571/genetic-risk-factors-for-cognitive-decline-in-parkinson-s-disease-a-review-of-the-literature
#16
REVIEW
E S Fagan, L Pihlstrøm
Parkinson's disease is a highly heterogeneous disorder, where genetic factors are likely to contribute to clinical variability, including susceptibility to cognitive impairment and dementia. Monogenic forms of parkinsonism show distinct cognitive profiles, yet less is known about the impact of common genetic variants on cognition in sporadic Parkinson's disease. In a systematic review of the literature, the current results from genetic association studies of cognitive outcomes are summarized and prospects and challenges for future studies are discussed...
April 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/28213071/pla2g6-accumulates-in-lewy-bodies-in-park14-and-idiopathic-parkinson-s-disease
#17
Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi
The histopathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is the occurrence of insoluble fibrillary aggregates known as Lewy bodies, in which phosphorylated α-synuclein (α-syn) is a major component. To date, familial PD-linked gene products, including α-syn, parkin, PINK-1, DJ-1 and LRRK2, are known to be involved in Lewy body formation. Phospholipase A2, group VI (PLA2G6) is the causative gene for PARK14-linked parkinsonism (PARK14), a familial form of juvenile-onset dystonia parkinsonism...
February 14, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28205494/language-deficits-as-a-preclinical-window-into-parkinson-s-disease-evidence-from-asymptomatic-parkin-and-dardarin-mutation-carriers
#18
Adolfo M García, Lucas Sedeño, Natalia Trujillo, Yamile Bocanegra, Diana Gomez, David Pineda, Andrés Villegas, Edinson Muñoz, William Arias, Agustín Ibáñez
OBJECTIVES: The worldwide spread of Parkinson's disease (PD) calls for sensitive and specific measures enabling its early (or, ideally, preclinical) detection. Here, we use language measures revealing deficits in PD to explore whether similar disturbances are present in asymptomatic individuals at risk for the disease. METHODS: We administered executive, semantic, verb-production, and syntactic tasks to sporadic PD patients, genetic PD patients with PARK2 (parkin) or LRRK2 (dardarin) mutation, asymptomatic first-degree relatives of the latter with similar mutations, and socio-demographically matched controls...
February 2017: Journal of the International Neuropsychological Society: JINS
https://www.readbyqxmd.com/read/28202711/structural-interface-between-lrrk2-and-14-3-3-protein
#19
Loes Stevers, Rens de Vries, Richard Doveston, Lech-Gustav Milroy, Luc Brunsveld, Christian Ottmann
Binding of 14-3-3 proteins to LRRK2 is known to be impaired by a number of Parkinson's disease (PD)-relevant mutations. Abrogation of this interaction is connected to enhanced LRRK2 kinase activity which in turn is implicated in increased ubiquitination of LRRK2, accumulation of LRRK2 into inclusion bodies and reduction of neurite length. Hence, the interaction between 14-3-3 and LRRK2 is of significant interest as a possible drug target for the treatment of PD. However, LRRK2 possesses multiple sites that upon phosphorylation can bind to 14-3-3, thus rendering the interaction relatively complex...
February 15, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28202680/cross-talk-between-lrrk2-and-pka-implication-for-parkinson-s-disease
#20
REVIEW
Elisa Greggio, Luigi Bubacco, Isabella Russo
Evidence indicates that leucine-rich repeat kinase 2 (LRRK2) controls multiple processes in neurons and glia cells. Deregulated LRRK2 activity due to gene mutation represents the most common cause of autosomal dominant Parkinson's disease (PD). Protein kinase A (PKA)-mediated signaling is a key regulator of brain function. PKA-dependent pathways play an important role in brain homeostasis, neuronal development, synaptic plasticity, control of microglia activation and inflammation. On the other hand, a decline of PKA signaling was shown to contribute to the progression of several neurodegenerative diseases, including PD...
February 8, 2017: Biochemical Society Transactions
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