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https://www.readbyqxmd.com/read/29329938/pipeline-to-gene-discovery-analysing-familial-parkinsonism-in-the-queensland-parkinson-s-project
#1
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/29325612/genetics-of-parkinson-disease
#2
Aloysius Domingo, Christine Klein
An understanding of the genetic etiology of Parkinson disease (PD) has become imperative for the modern-day neurologist. Although genetic forms cause only a minority of PD, the disease mechanisms they elucidate advance the understanding of idiopathic cases. Moreover, recently identified susceptibility variants contribute to complex-etiology PD and broaden the contribution of genetics beyond familial and early-onset cases. Dominantly inherited monogenic forms mimic idiopathic PD and are caused by mutations or copy number variations of SNCA, LRRK2, and VPS35...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29323027/micrornas-in-parkinson-s-disease-and-emerging-therapeutic-targets
#3
REVIEW
Bridget Martinez, Philip V Peplow
Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain cortex. Over 90% of patients with PD have sporadic PD and occur in people with no known family history of the disorder. Currently there is no cure for PD. Treatment with medications to increase dopamine relieves the symptoms but does not slow down or reverse the damage to neurons in the brain. Increasing evidence points to inflammation as a chief mediator of PD with inflammatory response mechanisms, involving microglia and leukocytes, activated following loss of dopaminergic neurons...
December 2017: Neural Regeneration Research
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
#4
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/29321020/meta-analysis-of-human-gene-expression-in-response-to-mycobacterium-tuberculosis-infection-reveals-potential-therapeutic-targets
#5
Zhang Wang, Seda Arat, Michal Magid-Slav, James R Brown
BACKGROUND: With the global emergence of multi-drug resistant strains of Mycobacterium tuberculosis, new strategies to treat tuberculosis are urgently needed such as therapeutics targeting potential human host factors. RESULTS: Here we performed a statistical meta-analysis of human gene expression in response to both latent and active pulmonary tuberculosis infections from nine published datasets. We found 1655 genes that were significantly differentially expressed during active tuberculosis infection...
January 10, 2018: BMC Systems Biology
https://www.readbyqxmd.com/read/29315334/immune-related-genetic-enrichment-in-frontotemporal-dementia-an-analysis-of-genome-wide-association-studies
#6
Iris Broce, Celeste M Karch, Natalie Wen, Chun C Fan, Yunpeng Wang, Chin Hong Tan, Naomi Kouri, Owen A Ross, Günter U Höglinger, Ulrich Muller, John Hardy, Parastoo Momeni, Christopher P Hess, William P Dillon, Zachary A Miller, Luke W Bonham, Gil D Rabinovici, Howard J Rosen, Gerard D Schellenberg, Andre Franke, Tom H Karlsen, Jan H Veldink, Raffaele Ferrari, Jennifer S Yokoyama, Bruce L Miller, Ole A Andreassen, Anders M Dale, Rahul S Desikan, Leo P Sugrue
BACKGROUND: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. METHODS AND FINDINGS: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis...
January 2018: PLoS Medicine
https://www.readbyqxmd.com/read/29309488/progression-in-the-lrrk2-asssociated-parkinson-disease-population
#7
Rachel Saunders-Pullman, Anat Mirelman, Roy N Alcalay, Cuiling Wang, Roberto A Ortega, Deborah Raymond, Helen Mejia-Santana, Martha Orbe-Reilly, Brooke A Johannes, Avner Thaler, Laurie Ozelius, Avi Orr-Urtreger, Karen S Marder, Nir Giladi, Susan B Bressman
Importance: Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials. Objective: To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation. Design, Setting, and Participants: A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016...
January 8, 2018: JAMA Neurology
https://www.readbyqxmd.com/read/29308544/the-lrrk2-signalling-system
#8
REVIEW
Alice Price, Claudia Manzoni, Mark R Cookson, Patrick A Lewis
The LRRK2 gene is a major contributor to genetic risk for Parkinson's disease and understanding the biology of the leucine-rich repeat kinase 2 (LRRK2, the protein product of this gene) is an important goal in Parkinson's research. LRRK2 is a multi-domain, multi-activity enzyme and has been implicated in a wide range of signalling events within the cell. Because of the complexities of the signal transduction pathways in which LRRK2 is involved, it has been challenging to generate a clear idea as to how mutations and disease associated variants in this gene are altered in disease...
January 8, 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29307545/pfe-360-induced-lrrk2-inhibition-induces-reversible-non-adverse-renal-changes-in-rats
#9
Michael Aagaard Andersen, Karen Malene Wegener, Steen Larsen, Lassina Badolo, Garrick Paul Smith, Ross Jeggo, Poul Henning Jensen, Florence Sotty, Kenneth Vielsted Christensen, Annemette Thougaard
Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no existing therapeutic approach to delay or stop progression. Genetic, biochemical and pre-clinical studies have provided evidence that leucine-rich-repeat-kinase-2 (LRRK2) kinase is involved in the pathogenesis of PD, and small molecule LRRK2 inhibitors represent a novel potential therapeutic approach. However, potentially adverse target-related effects have been discovered in the lung and kidneys of LRRK2 knock-out (ko) mice and rats...
January 4, 2018: Toxicology
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
#10
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/29305429/back-to-the-future-new-target-validated-rab-antibodies-for-evaluating-lrrk2-signalling-in-cell-biology-and-parkinson-s-disease
#11
Patrick A Eyers
The addition of phosphate groups to substrates allows protein kinases to regulate a myriad of biological processes, and contextual analysis of protein-bound phosphate is important for understanding how kinases contribute to physiology and disease. Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase linked to familial and sporadic cases of Parkinson's disease (PD). Recent work established that multiple Rab GTPases are physiological substrates of LRRK2, with Rab10 in particular emerging as a human substrate whose site-specific phosphorylation mirrors hyperactive LRRK2 lesions associated with PD...
January 5, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29286425/rab10-phosphorylation-detection-by-lrrk2-activity-using-sds-page-with-a-phosphate-binding-tag
#12
Genta Ito, Taisuke Tomita
Mutations in leucine-rich repeat kinase 2 (LRRK2) have been shown to be linked with familial Parkinson's disease (FPD). Since abnormal activation of the kinase activity of LRRK2 has been implicated in the pathogenesis of PD, it is essential to establish a method to evaluate the physiological levels of the kinase activity of LRRK2. Recent studies revealed that LRRK2 phosphorylates members of the Rab GTPase family, including Rab10, under physiological conditions. Although the phosphorylation of endogenous Rab10 by LRRK2 in cultured cells could be detected by mass spectrometry, it has been difficult to detect it by immunoblotting due to the poor sensitivity of currently available phosphorylation-specific antibodies for Rab10...
December 14, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29285276/pilot-study-molecular-risk-factors-for-diagnosing-sporadic-parkinson-s-disease-based-on-gene-expression-in-blood-in-mptp-induced-rhesus-monkeys
#13
Liangqin Shi, Chao Huang, Qihui Luo, Yu Xia, Heng Liu, Like Li, Wentao Liu, Wenjing Ma, Jing Fang, Li Tang, Wen Zeng, Zhengli Chen
Clinical diagnosis of Parkinson's disease (PD) is characterized by the classical features of tremor, bradykinesia and rigidity, which are present only when more than 70%-80% degeneration of dopaminergic (DA) neurons in the substantia nigra. The lack of means for early diagnosis of PD has elicited interest in searching for its risk factors, which, by now, are almost obtained at a single time point in PD process, and little developing risk factors, obtained from completely normal situation to the onset or even advanced stage of PD in individual person which could monitor the progress of PD, are present...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29249679/cognitive-profile-and-18f-fluorodeoxyglucose-pet-study-in-lrrk2-related-parkinson-s-disease
#14
Anna De Rosa, Silvio Peluso, Natascia De Lucia, Paola Russo, Ida Annarumma, Marcello Esposito, Fiore Manganelli, Arturo Brunetti, Giuseppe De Michele, Sabina Pappatà
INTRODUCTION: LRRK2 gene mutations underlie the most common mendelian form of Parkinson's Disease (PD), designated PARK8, that shows clinical features similar to those in idiopathic PD (IPD). We assessed the cognitive functions and the cerebral metabolism measured with 18F-fluorodeoxyglucose (FDG)-PET in PARK8 patients compared with IPD. PATIENTS AND METHODS: We enrolled eight PARK8 patients and eight IPD patients, comparable for onset age, stage, severity and duration of disease...
December 9, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29248340/role-of-lrrk2-and-snca-in-autosomal-dominant-parkinson-s-disease-in-turkey
#15
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/29246723/familial-knockin-mutation-of-lrrk2-causes-lysosomal-dysfunction-and-accumulation-of-endogenous-insoluble-%C3%AE-synuclein-in-neurons
#16
Jason Schapansky, Saurabh Khasnavis, Mark P DeAndrade, Jonathan D Nardozzi, Samuel R Falkson, Justin D Boyd, John B Sanderson, Tim Bartels, Heather L Melrose, Matthew J LaVoie
Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble α-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function...
December 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29241968/case-control-analysis-of-leucine-rich-repeat-kinase-2-protective-variants-in-alzheimer-s-disease
#17
Adeline S L Ng, Ebonne Y L Ng, Yi Jayne Tan, Nagaendran Kandiah, Juan Zhou, Shahul Hameed, Simon K S Ting, Eng-King Tan
Amyloid is the main pathological substrate of Alzheimer's disease (AD) and has been described in leucine-rich repeat kinase 2 (LRRK2) carriers with Parkinson's disease. LRRK2 has been linked with amyloid precursor protein pathways in neurodegeneration. Two common LRRK2 variants, R1398H and N551K, have been shown to be protective in multiple Parkinson's disease cohorts. We hypothesized that R1398H and N551K may be protective in AD. In a case-control study involving 1390 subjects (719 controls and 671 AD cases), R1398H was demonstrated in 16...
November 27, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29241837/kinases-in-synaptic-development-and-neurological-diseases
#18
REVIEW
Lucas Baltussen, Flavia Rosianu, Sila Ultanir
Neuronal morphogenesis and synapse development is essential for building a functioning nervous system and defects in these processes are associated with neurological disorders. Our understanding of molecular components and signalling events that contribute to neuronal development and pathogenesis is limited. Genes associated with neurodevelopmental and neurodegenerative diseases provide entry points for elucidating molecular events that contribute to these conditions. Several protein kinases, enzymes that regulate protein function by phosphorylating their substrates, are genetically linked to neurological disorders...
December 11, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/29228965/genetic-polymorphism-in-atg16l1-gene-is-associated-with-adalimumab-use-in-inflammatory-bowel-disease
#19
V J A A Nuij, M P Peppelenbosch, C J van der Woude, G M Fuhler
BACKGROUND: The role of single nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease (IBD) is gaining interest. With the advent of novel therapies, personalized treatment in IBD is a future goal. We wondered whether IBD-associated SNPs are able to predict response to anti-TNFα treatment. METHODS: Data on treatment use and primary response, loss of response and side effects to anti-TNFα treatments were retrieved for 570 IBD patients. rs13361189 (IRGM), rs10210302 (ATG16L1), rs2066844, rs2066845, rs2066847 (NOD2), rs35873774 (XBP1), rs11175593 (LRRK2), rs11465804 (IL23R), rs2301436 (CCR6), rs744166 (STAT3) and rs4821544 (NCF4) SNP status were determined...
December 11, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29223392/parkinson-s-disease-associated-mutant-lrrk2-phosphorylates-rab7l1-and-modifies-trans-golgi-morphology
#20
Tetta Fujimoto, Tomoki Kuwahara, Tomoya Eguchi, Maria Sakurai, Tadayuki Komori, Takeshi Iwatsubo
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the major genetic cause of autosomal-dominantly inherited Parkinson's disease. LRRK2 is implicated in the regulation of intracellular trafficking, neurite outgrowth and PD risk in connection with Rab7L1, a putative interactor of LRRK2. Recently, a subset of Rab GTPases have been reported as substrates of LRRK2. Here we examine the kinase activity of LRRK2 on Rab7L1 in situ in cells. Phos-tag analyses and metabolic labeling assays revealed that LRRK2 readily phosphorylates Golgi-localized wild-type Rab7L1 but not mutant forms that are distributed in the cytoplasm...
December 6, 2017: Biochemical and Biophysical Research Communications
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