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https://www.readbyqxmd.com/read/29665080/clustering-of-motor-and-nonmotor-traits-in-leucine-rich-repeat-kinase-2-g2019s-parkinson-s-disease-nonparkinsonian-relatives-a-multicenter-family-study
#1
Tiago A Mestre, Claustre Pont-Sunyer, Farah Kausar, Naomi P Visanji, Taneera Ghate, Barbara S Connolly, Carmen Gasca-Salas, Drew S Kern, Jennifer Jain, Elizabeth J Slow, Achinoam Faust-Socher, Meike Kasten, Pettarusp M Wadia, Cindy Zadikoff, Prakash Kumar, Ronald M de Bie, Teri Thomsen, Anthony E Lang, Birgitt Schüle, Christine Klein, Eduardo Tolosa, Connie Marras
OBJECTIVES: The objective of this study was to determine phenotypic features that differentiate nonparkinsonian first-degree relatives of PD leucine-rich repeat kinase 2 (LRRK2) G2019S multiplex families, regardless of carrier status, from healthy controls because nonparkinsonian individuals in multiplex families seem to share a propensity to present neurological features. METHODS: We included nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases and unrelated healthy controls participating in established multiplex family LRRK2 cohorts...
April 17, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29627023/motor-and-non-motor-features-of-parkinson-s-disease-in-lrrk2-g2019s-carriers-versus-matched-controls
#2
Steven A Gunzler, David E Riley, Shu G Chen, Curtis M Tatsuoka, William M Johnson, John J Mieyal, Ellen M Walter, Christina M Whitney, I Jung Feng, Harry Owusu-Dapaah, Shivam O Mittal, Amy L Wilson-Delfosse
INTRODUCTION: LRRK2 G2019S mutation carriers with Parkinson's disease (PD) have been generally indistinguishable from those with idiopathic PD, with the exception of variable differences in some motor and non-motor domains, including cognition, gait, and balance. LRRK2 G2019S is amongst the most common genetic etiologies for PD, particularly in Ashkenazi Jewish (AJ) populations. METHODS: This cross-sectional data collection study sought to clarify the phenotype of LRRK2 G2019S mutation carriers with PD...
May 15, 2018: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/29603409/application-of-the-movement-disorder-society-prodromal-criteria-in-healthy-g2019s-lrrk2-carriers
#3
Anat Mirelman, Rachel Saunders-Pullman, Roy N Alcalay, Shiran Shustak, Avner Thaler, Tanya Gurevich, Deborah Raymond, Helen Mejia-Santana, Martha Orbe Reilly, Laurie Ozelius, Lorraine Clark, Mali Gana-Weisz, Anat Bar-Shira, Avi Orr-Utreger, Susan B Bressman, Karen Marder, Nir Giladi
BACKGROUND: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD. OBJECTIVES: We aimed to evaluate, for the first time, the criteria in first-degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters. METHODS: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49...
March 30, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29550548/age-related-pathology-after-adenoviral-overexpression-of-the-leucine-rich-repeat-kinase-2-in-the-mouse-striatum
#4
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
https://www.readbyqxmd.com/read/29519959/p62-sqstm1-is-a-novel-leucine-rich-repeat-kinase-2-lrrk2-substrate-that-enhances-neuronal-toxicity
#5
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
https://www.readbyqxmd.com/read/29473656/%C3%AE-synuclein-snca-but-not-dynamin-3-dnm3-influences-age-at-onset-of-leucine-rich-repeat-kinase-2-lrrk2-parkinson-s-disease-in-spain
#6
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
https://www.readbyqxmd.com/read/29439717/dysregulated-phosphorylation-of-rab-gtpases-by-lrrk2-induces-neurodegeneration
#7
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
#8
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
#9
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...
April 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
#10
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
#11
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
#12
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
#13
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...
April 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
#14
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
#15
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...
April 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
#16
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-before-the-onset-of-motor-dysfunction-with-5-ht-1a-receptor-upregulation-in-mice
#17
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, including increased dopaminergic neurodegeneration and Lewy bodies, is indistinguishable from that of idiopathic PD. The subtle nonmotor phenotypes of LRRK2 mutation-related PD 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...
February 14, 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
#18
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...
March 2018: 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
#19
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
#20
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...
January 15, 2018: Human Molecular Genetics
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