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https://www.readbyqxmd.com/read/29439717/dysregulated-phosphorylation-of-rab-gtpases-by-lrrk2-induces-neurodegeneration
#1
Ga Ram Jeong, Eun-Hae Jang, Jae Ryul Bae, Soyoung Jun, Ho Chul Kang, Chi-Hu Park, Joo-Ho Shin, Yukio Yamamoto, Keiko Tanaka-Yamamoto, Valina L Dawson, Ted M Dawson, Eun-Mi Hur, Byoung Dae Lee
BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). Elevated kinase activity is associated with LRRK2 toxicity, but the substrates that mediate neurodegeneration remain poorly defined. Given the increasing evidence suggesting a role of LRRK2 in membrane and vesicle trafficking, here we systemically screened Rab GTPases, core regulators of vesicular dynamics, as potential substrates of LRRK2 and investigated the functional consequence of such phosphorylation in cells and in vivo...
February 13, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29434188/dopamine-d2-receptor-mediated-neuroprotection-in-a-g2019s-lrrk2-genetic-model-of-parkinson-s-disease
#2
Alessandro Tozzi, Michela Tantucci, Saverio Marchi, Petra Mazzocchetti, Michele Morari, Paolo Pinton, Andrea Mancini, Paolo Calabresi
Parkinson's disease (PD) is a neurodegenerative disorder in which genetic and environmental factors synergistically lead to loss of midbrain dopamine (DA) neurons. Mutation of leucine-rich repeated kinase2 (Lrrk2) genes is responsible for the majority of inherited familial cases of PD and can also be found in sporadic cases. The pathophysiological role of this kinase has to be fully understood yet. Hyperactivation of Lrrk2 kinase domain might represent a predisposing factor for both enhanced striatal glutamatergic release and mitochondrial vulnerability to environmental factors that are observed in PD...
February 12, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29414418/generation-of-an-induced-pluripotent-stem-cell-line-csc-41-from-a-parkinson-s-disease-patient-carrying-a-p-g2019s-mutation-in-the-lrrk2-gene
#3
Ana Marote, Yuriy Pomeshchik, Anna Collin, Stefano Goldwurm, Nuno J Lamas, Luísa Pinto, António J Salgado, Laurent Roybon
The leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation is the most common genetic cause of Parkinson's disease (PD). An induced pluripotent stem cell (iPSC) line CSC-41 was generated from a 75-year old patient diagnosed with PD caused by a p.G2019S mutation in LRRK2. Skin fibroblasts were reprogrammed using a non-integrating Sendai virus-based technology to deliver OCT3/4, SOX2, c-MYC and KLF4 transcription factors. The generated iPSC line exhibits expression of common pluripotency markers, differentiates into the three germ layers and has a normal karyotype...
February 2, 2018: Stem Cell Research
https://www.readbyqxmd.com/read/29402177/in-vitro-modeling-of-leucine-rich-repeat-kinase-2-lrrk2-g2019s-mediated-parkinson-s-disease-pathology
#4
Scott C Vermilyea, Marina Emborg
Leucine-rich repeat kinase 2 (LRRK2) G2019S (glycine to serine) is the most common mutation associated with sporadic and familial Parkinson's disease (PD) with 80% penetrance by age 70. This mutation is found worldwide, with up to 40% of individuals in the North African Arab population carrying the mutation. Induced pluripotent stem cells (iPSCs) derived from fibroblasts of patients carrying the LRRK2 G2019S mutation have been a critical source of cells for generating dopaminergic neurons and studying G2019S-related pathology...
February 5, 2018: Stem Cells and Development
https://www.readbyqxmd.com/read/29387348/age-induced-neuronal-cell-death-is-enhanced-in-g2019s-lrrk2-mutation-with-increased-rage-expression
#5
Hyun Jin Cho, Chengsong Xie, Huaibin Cai
Background: Leucine-rich repeat kinase 2 (LRRK2) mutations represent the most common genetic cause of sporadic and familial Parkinson's disease (PD). Especially, LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD. Advanced glycation end products (AGEs) are produced in high amounts in diabetes and diverse aging-related disorders, such as cardiovascular disease, renal disease, and neurological disease. AGEs trigger intracellular signaling pathway associated with oxidative stress and inflammation as well as cell death...
2018: Translational Neurodegeneration
https://www.readbyqxmd.com/read/29386392/robust-kinase-and-age-dependent-dopaminergic-and-norepinephrine-neurodegeneration-in-lrrk2-g2019s-transgenic-mice
#6
Yulan Xiong, Stewart Neifert, Senthilkumar S Karuppagounder, Qinfang Liu, Jeannette N Stankowski, Byoung Dae Lee, Han Seok Ko, Yunjong Lee, Jonathan C Grima, Xiaobo Mao, Haisong Jiang, Sung-Ung Kang, Deborah A Swing, Lorraine Iacovitti, Lino Tessarollo, Ted M Dawson, Valina L Dawson
Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson's disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase-dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons...
January 31, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29369793/alpha-galactosidase-a-activity-in-parkinson-s-disease
#7
R N Alcalay, P Wolf, O A Levy, U J Kang, C Waters, S Fahn, B Ford, S H Kuo, N Vanegas, H Shah, C Liong, S Narayan, M W Pauciulo, W C Nichols, Z Gan-Or, G A Rouleau, W K Chung, P Oliva, J Keutzer, K Marder, X K Zhang
Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University...
January 21, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29369408/exploring-the-functional-impact-of-mutational-drift-in-lrrk2-gene-identification-of-specific-inhibitors-for-the-treatment-of-parkinson-disease
#8
Nagasundaram Nagarajan, Jaynthy Chellam, Rajaretinam Rajesh Kannan
Parkinson's disease (PD) is a disorder of the central nervous system that is caused due to the death of the dopaminergic neurons in the region of the brain called substantia nigra. Mutations in LRRK2 genes are associated with disease condition and it's been reported as crucial factor for drug resistance. Identification of deleterious mutations and studying the structural and functional impact of such mutations may lead to the identification of potential selective inhibitors. In this study, we analyzed 52 PD associated mutations, among that 20 were identified as highly deleterious...
January 25, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29329938/pipeline-to-gene-discovery-analysing-familial-parkinsonism-in-the-queensland-parkinson-s-project
#9
Steven R Bentley, Stephanie Bortnick, Ilaria Guella, Javed Y Fowdar, Peter A Silburn, Stephen A Wood, Matthew J Farrer, George D Mellick
INTRODUCTION: Family based study designs provide an informative resource to identify disease-causing mutations. The Queensland Parkinson's Project (QPP) has been involved in numerous genetic screening studies; however, details of the families enrolled into the register have not been comprehensively reported. This article characterises the families enrolled in the QPP and summarises monogenic forms of hereditary Parkinsonism found in the register. METHOD: The presence of pathogenic point mutations and copy number variations (CNVs) were, generally, screened in a sample of over 1000 PD patients from the total of 1725...
January 3, 2018: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29321258/functional-variants-in-the-lrrk2-gene-confer-shared-effects-on-risk-for-crohn-s-disease-and-parkinson-s-disease
#10
Ken Y Hui, Heriberto Fernandez-Hernandez, Jianzhong Hu, Adam Schaffner, Nathan Pankratz, Nai-Yun Hsu, Ling-Shiang Chuang, Shai Carmi, Nicole Villaverde, Xianting Li, Manual Rivas, Adam P Levine, Xiuliang Bao, Philippe R Labrias, Talin Haritunians, Darren Ruane, Kyle Gettler, Ernie Chen, Dalin Li, Elena R Schiff, Nikolas Pontikos, Nir Barzilai, Steven R Brant, Susan Bressman, Adam S Cheifetz, Lorraine N Clark, Mark J Daly, Robert J Desnick, Richard H Duerr, Seymour Katz, Todd Lencz, Richard H Myers, Harry Ostrer, Laurie Ozelius, Haydeh Payami, Yakov Peter, John D Rioux, Anthony W Segal, William K Scott, Mark S Silverberg, Jeffery M Vance, Iban Ubarretxena-Belandia, Tatiana Foroud, Gil Atzmon, Itsik Pe'er, Yiannis Ioannou, Dermot P B McGovern, Zhenyu Yue, Eric E Schadt, Judy H Cho, Inga Peter
Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10-10) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3...
January 10, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29305532/lrrk2-g2019s-induces-anxiety-depression-like-behavior-prior-to-the-onset-of-motor-dysfunction-with-5-ht1a-receptor-upregulation-in-mice
#11
Juhee Lim, Yeojin Bang, Jong-Hyun Choi, Arum Han, Min-Soo Kwon, Kwang Hyeon Liu, Hyun Jin Choi
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD). The neuropathology of LRRK2 mutation-related PD is indistinguishable from that of idiopathic PD, including increased dopaminergic neurodegeneration and Lewy bodies, but its subtle non-motor phenotypes have not been fully evaluated. In the present study, we examined anxiety/depression-like behaviors and accompanying neurochemical changes in differently aged transgenic (Tg) mice expressing human mutant LRRK2 G2019S...
January 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29248340/role-of-lrrk2-and-snca-in-autosomal-dominant-parkinson-s-disease-in-turkey
#12
Christoph Kessler, Burcu Atasu, Hasmet Hanagasi, Javier Simón-Sánchez, Ann-Kathrin Hauser, Meltem Pak, Basar Bilgic, Nihan Erginel-Unaltuna, Hakan Gurvit, Thomas Gasser, Ebba Lohmann
INTRODUCTION: Mutations in the LRRK2 and alpha-synuclein (SNCA) genes are well-established causes of autosomal dominant Parkinson's disease (PD). However, their frequency differs widely between ethnic groups. Only three studies have screened all coding regions of LRRK2 and SNCA in European samples so far. In Turkey, the role of LRRK2 in Parkinson's disease has been studied fragmentarily, and the incidence of SNCA copy number variations is unknown. The purpose of this study is to determine the frequency of LRRK2 and SNCA mutations in autosomal dominant PD in Turkey...
December 9, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29214211/targeted-kinase-inhibition-relieves-slowness-and-tremor-in-a-drosophila-model-of-lrrk2-parkinson-s-disease
#13
Amy C Cording, Nicolas Shiaelis, Stavroula Petridi, C Adam Middleton, Laurence G Wilson, Christopher J H Elliott
In a number of Drosophila models of genetic Parkinson's disease (PD) flies climb more slowly than wild-type controls. However, this assay does not distinguish effects of PD-related genes on gravity sensation, "arousal", central pattern generation of leg movements, or muscle. To address this problem, we have developed an assay for the fly proboscis extension response (PER). This is attractive because the PER has a simple, well-identified reflex neural circuit, in which sucrose sensing neurons activate a pair of "command interneurons", and thence motoneurons whose activity contracts the proboscis muscle...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/29177506/lrrk2-phosphorylates-membrane-bound-rabs-and-is-activated-by-gtp-bound-rab7l1-to-promote-recruitment-to-the-trans-golgi-network
#14
Zhiyong Liu, Nicole Bryant, Ravindran Kumaran, Alexandra Beilina, Asa Abeliovich, Mark R Cookson, Andrew B West
Human genetic studies implicate LRRK2 and Rab7L1 in susceptibility to Parkinson disease (PD). These two genes function in the same pathway, as knockout of Rab7L1 results in phenotypes similar to LRRK2 knockout, and studies in cells and model organisms demonstrate LRRK2 and Rab7L1 interact in the endolysosomal system. Recently, a subset of Rab proteins have been identified as LRRK2 kinase substrates. Herein, we find that Rab8, Rab10, and Rab7L1 must be membrane and GTP-bound for LRRK2 phosphorylation. LRRK2 mutations that cause PD including R1441C, Y1699C, and G2019S all increase LRRK2 phosphorylation of Rab7L1 four-fold over wild-type LRRK2 in cells, resulting in the phosphorylation of nearly one-third the available Rab7L1 protein in cells...
November 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29166931/elevated-lrrk2-autophosphorylation-in-brain-derived-and-peripheral-exosomes-in-lrrk2-mutation-carriers
#15
Shijie Wang, Zhiyong Liu, Tao Ye, Omar S Mabrouk, Tyler Maltbie, Jan Aasly, Andrew B West
Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease (PD). LRRK2 mutations increase LRRK2 kinase activities that may increase levels of LRRK2 autophosphorylation at serine 1292 (pS1292) and neurotoxicity in model systems. pS1292-LRRK2 protein can be packaged into exosomes and measured in biobanked urine. Herein we provide evidence that pS1292-LRRK2 protein is robustly expressed in cerebral spinal fluid (CSF) exosomes. In a novel cohort of Norwegian subjects with and without the G2019S-LRRK2 mutation, with and without PD, we quantified levels of pS1292-LRRK2, total LRRK2, and other exosome proteins in urine from 132 subjects and in CSF from 82 subjects...
November 22, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29163333/mutation-analysis-of-consanguineous-moroccan-patients-with-parkinson-s-disease-combining-microarray-and-gene-panel
#16
Ahmed Bouhouche, Christelle Tesson, Wafaa Regragui, Mounia Rahmani, Valérie Drouet, Houyam Tibar, Zouhayr Souirti, Rafiqua Ben El Haj, Naima Bouslam, Mohamed Yahyaoui, Alexis Brice, Ali Benomar, Suzanne Lesage
During the last two decades, 15 different genes have been reported to be responsible for the monogenic form of Parkinson's disease (PD), representing a worldwide frequency of 5-10%. Among them, 10 genes have been associated with autosomal recessive PD, with PRKN and PINK1 being the most frequent. In a cohort of 145 unrelated Moroccan PD patients enrolled since 2013, 19 patients were born from a consanguineous marriage, of which 15 were isolated cases and 4 familial. One patient was homozygous for the common LRRK2 G2019S mutation and the 18 others who did not carry this mutation were screened for exon rearrangements in the PRKN gene using Affymetrix Cytoscan HD microarray...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/29159192/sex-differences-in-lrrk2-g2019s-and-idiopathic-parkinson-s-disease
#17
Marta San Luciano, Cuiling Wang, Roberto A Ortega, Nir Giladi, Karen Marder, Susan Bressman, Rachel Saunders-Pullman
Objective: To evaluate sex differences and the relative effect of G2019S LRRK2 mutations in Parkinson's disease (PD). Methods: 530 LRRK2 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and LRRK2 PD; and features were compared between IPD and LRRK2 PD separately for men and women...
November 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29129681/decreased-sirtuin-deacetylase-activity-in-lrrk2-g2019s-ipsc-derived-dopaminergic-neurons
#18
Andrew J Schwab, Samantha L Sison, Michael R Meade, Katarzyna A Broniowska, John A Corbett, Allison D Ebert
Mitochondrial changes have long been implicated in the pathogenesis of Parkinson's disease (PD). The glycine to serine mutation (G2019S) in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause for PD and has been shown to impair mitochondrial function and morphology in multiple model systems. We analyzed mitochondrial function in LRRK2 G2019S induced pluripotent stem cell (iPSC)-derived neurons to determine whether the G2019S mutation elicits similar mitochondrial deficits among central and peripheral nervous system neuron subtypes...
October 31, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29127256/development-of-phospho-specific-rab-protein-antibodies-to-monitor-in-vivo-activity-of-the-lrrk2-parkinson-s-disease-kinase
#19
Pawel Lis, Sophie Burel, Martin Steger, Matthias Mann, Fiona Brown, Federico Diez, Francesca Tonelli, Janice L Holton, Philip Winglok Ho, Shu-Leong Ho, Meng-Yun Chou, Nicole K Polinski, Terina N Martinez, Paul Davies, Dario R Alessi
Mutations that activate the LRRK2 protein kinase, predispose to Parkinson's disease, suggesting that LRRK2 inhibitors might have therapeutic benefit. Recent work has revealed that LRRK2 phosphorylates a subgroup of 14 Rab proteins, including Rab10, at a specific residue located at the centre of its effector binding Switch-II motif. In this study, we analyse the selectivity and sensitivity of polyclonal and monoclonal phospho-specific antibodies raised against 9 different LRRK2 phosphorylated Rab proteins (Rab3A/3B/3C/3D, Rab5A/5B/5C, Rab8A/8B, Rab10, Rab12, Rab29[T71], Rab29[S72], Rab35 and Rab43)...
November 10, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29127255/interrogating-parkinson-s-disease-lrrk2-kinase-pathway-activity-by-assessing-rab10-phosphorylation-in-human-neutrophils
#20
Ying Fan, Andrew Jm Howden, Adil R Sarhan, Pawel Lis, Genta Ito, Terina N Martinez, Kathrin Brockmann, Thomas Gasser, Dario R Alessi, Esther M Sammler
There is compelling evidence for the role of LRRK2 and in particular its kinase function in Parkinson's disease. Orally bioavailable, brain penetrant and potent LRRK2 kinase inhibitors are in the later stages of clinical development. Here we describe a facile and robust assay to quantify LRRK2 kinase pathway activity by measuring LRRK2 mediated phosphorylation of Rab10 in human peripheral blood neutrophils. We use the selective MJFF-pRab10 monoclonal antibody recognising the Rab10 Thr73 phospho-epitope that is phosphorylated by LRRK2...
November 10, 2017: Biochemical Journal
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