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Leucine repeat rich kinase 2

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https://www.readbyqxmd.com/read/28420983/increased-oxidative-stress-markers-in-cerebrospinal-fluid-from-healthy-subjects-with-parkinson-s-disease-associated-lrrk2-gene-mutations
#1
David A Loeffler, Andrea C Klaver, Mary P Coffey, Jan O Aasly, Peter A LeWitt
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of inherited Parkinson's disease (PD). The most common PD-associated LRRK2 mutation, G2019S, induces increased production of reactive oxygen species in vitro. We therefore hypothesized that individuals with PD-associated LRRK2 mutations might have increased concentrations of oxidative stress markers and/or decreased total antioxidant capacity (TAC) in their cerebrospinal fluid (CSF). We measured two oxidative stress markers, namely 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostane (8-ISO), and TAC in CSF from LRRK2 mutation-bearing PD patients (LRRK2 PD = 19), sporadic PD patients (sPD = 31), and healthy control subjects with or without these mutations (LRRK2 CTL = 30, CTL = 27)...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28417442/mechanisms-of-gene-environment-interactions-in-parkinson-s-disease
#2
REVIEW
Sheila M Fleming
PURPOSE OF REVIEW: The purpose of the study was to discuss the main mechanisms associated with environmental and genetic factors that contribute to the development of Parkinson's disease (PD). RECENT FINDINGS: Novel genetic contributors to PD are being identified at a rapid pace in addition to novel environmental factors. The discovery of mutations in alpha-synuclein and leucine-rich repeat kinase 2 causing inherited forms of PD along with epidemiological, in vitro, and in vivo studies identifying herbicides, pesticides, and metals as risk factors have dramatically improved our understanding of mechanisms involved in the development of PD...
April 17, 2017: Current Environmental Health Reports
https://www.readbyqxmd.com/read/28409271/unique-presentation-of-cutis-laxa-with-leigh-like-syndrome-due-to-echs1-deficiency
#3
S Balasubramaniam, L G Riley, D Bratkovic, D Ketteridge, N Manton, M J Cowley, V Gayevskiy, T Roscioli, M Mohamed, T Gardeitchik, E Morava, J Christodoulou
Clinical finding of cutis laxa, characterized by wrinkled, redundant, sagging, nonelastic skin, is of growing significance due to its occurrence in several different inborn errors of metabolism (IEM). Metabolic cutis laxa results from Menkes syndrome, caused by a defect in the ATPase copper transporting alpha (ATP7A) gene; congenital disorders of glycosylation due to mutations in subunit 7 of the component of oligomeric Golgi (COG7)-congenital disorders of glycosylation (CDG) complex; combined disorder of N- and O-linked glycosylation, due to mutations in ATPase H+ transporting V0 subunit a2 (ATP6VOA2) gene; pyrroline-5-carboxylate reductase 1 deficiency; pyrroline-5-carboxylate synthase deficiency; macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome, due to Ras and Rab interactor 2 (RIN2) mutations; transaldolase deficiency caused by mutations in the transaldolase 1 (TALDO1) gene; Gerodermia osteodysplastica due to mutations in the golgin, RAB6-interacting (GORAB or SCYL1BP1) gene; and mitogen-activated pathway (MAP) kinase defects, caused by mutations in several genes [protein tyrosine phosphatase, non-receptor-type 11 (PTPN11), RAF, NF, HRas proto-oncogene, GTPase (HRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), MEK1/2, KRAS proto-oncogene, GTPase (KRAS), SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), leucine rich repeat scaffold protein (SHOC2), NRAS proto-oncogene, GTPase (NRAS), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)], which regulate the Ras-MAPK cascade...
April 13, 2017: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/28408707/admixture-mapping-of-subclinical-atherosclerosis-and-subsequent-clinical-events-among-african-americans-in-2-large-cohort-studies
#4
Aditi Shendre, Howard Wiener, Marguerite R Irvin, Degui Zhi, Nita A Limdi, Edgar T Overton, Christina L Wassel, Jasmin Divers, Jerome I Rotter, Wendy S Post, Sadeep Shrestha
BACKGROUND: Local ancestry may contribute to the disproportionate burden of subclinical and clinical cardiovascular disease among admixed African Americans compared with other populations, suggesting a rationale for admixture mapping. METHODS AND RESULTS: We estimated local European ancestry (LEA) using Local Ancestry inference in adMixed Populations using Linkage Disequilibrium method (LAMP-LD) and evaluated the association with common carotid artery intima-media thickness (cCIMT) using multivariable linear regression analysis among 1554 African Americans from MESA (Multi-Ethnic Study of Atherosclerosis)...
April 2017: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/28384649/differential-cle-peptide-perception-by-plant-receptors-implicated-from-structural-and-functional-analyses-of-tdif-tdr-interactions
#5
Zhijie Li, Sayan Chakraborty, Guozhou Xu
Tracheary Element Differentiation Inhibitory Factor (TDIF) belongs to the family of post-translationally modified CLE (CLAVATA3/embryo surrounding region (ESR)-related) peptide hormones that control root growth and define the delicate balance between stem cell proliferation and differentiation in SAM (shoot apical meristem) or RAM (root apical meristem). In Arabidopsis, Tracheary Element Differentiation Inhibitory Factor Receptor (TDR) and its ligand TDIF signaling pathway is involved in the regulation of procambial cell proliferation and inhibiting its differentiation into xylem cells...
2017: PloS One
https://www.readbyqxmd.com/read/28383562/vps35-regulates-parkin-substrate-aimp2-toxicity-by-facilitating-lysosomal-clearance-of-aimp2
#6
Seung Pil Yun, Hyojung Kim, Sangwoo Ham, Seung-Hwan Kwon, Gum Hwa Lee, Joo-Ho Shin, Sang Hun Lee, Han Seok Ko, Yunjong Lee
Vacuolar protein sorting-associated protein 35 (VPS35) is involved in retrograde transport of proteins from endosomes to trans-Golgi network. Gene mutations in VPS35 are linked to autosomal dominant late-onset Parkinson's disease (PD). Although the identification of VPS35 mutations has provided novel insight about its interactions with several PD-associated genes including leucine-rich repeat kinase 2 (LRRK2) and α-synuclein, little information is available about the molecular mechanisms of cell death downstream of VPS35 dysfunction...
April 6, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28370517/the-prodromal-phase-of-leucine-rich-repeat-kinase-2-associated-parkinson-disease-clinical-and-imaging-studies
#7
Claustre Pont-Sunyer, Eduardo Tolosa, Chelsea Caspell-Garcia, Christopher Coffey, Roy N Alcalay, Piu Chan, John E Duda, Maurizio Facheris, Rubén Fernández-Santiago, Kenneth Marek, Francisco Lomeña, Connie Marras, Elisabet Mondragon, Rachel Saunders-Pullman, Bjorg Waro
BACKGROUND: Asymptomatic, nonmanifesting carriers of leucine-rich repeat kinase 2 mutations are at increased risk of developing PD. Clinical and neuroimaging features may be associated with gene carriage and/or may demarcate individuals at greater risk for phenoconversion to PD. OBJECTIVES: To investigate clinical and dopamine transporter single-photon emission computed tomography imaging characteristics of leucine-rich repeat kinase 2 asymptomatic carriers. METHODS: A total of 342 carriers' and 259 noncarriers' relatives of G2019S leucine-rich repeat kinase 2/PD patients and 39 carriers' and 31 noncarriers' relatives of R1441G leucine-rich repeat kinase 2/PD patients were evaluated...
March 28, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28353288/small-molecule-inhibitors-of-lrrk2
#8
John M Hatcher, Hwan Geun Choi, Dario R Alessi, Nathanael S Gray
Mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been genetically and functionally linked to Parkinson's disease (PD). The kinase activity of LRRK2 is increased by pathogenic mutations; therefore, modulation of LRRK2 kinase activity by a selective small-molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. This chapter presents a historical overview of the development and bioactivity of several small-molecule LRRK2 inhibitors that have been used to inhibit LRRK2 kinase activity in vitro or in vivo...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28353285/lrrk2-and-the-lrrktosome-at-the-crossroads-of-programmed-cell-death-clues-from-rip-kinase-relatives
#9
Hardy J Rideout, Diane B Re
Since its cloning and identification in 2004, considerable gains have been made in the understanding of the basic functionality of leucine-rich repeat kinase 2 (LRRK2), including its kinase and GTPase activities, its protein interactors and subcellular localization, and its expression in the CNS and peripheral tissues. However, the mechanism(s) by which expression of mutant forms of LRRK2 lead to the death of dopaminergic neurons of the ventral midbrain remains largely uncharacterized. Because of its complex domain structure, LRRK2 exhibits similarities with multiple protein families including ROCO proteins, as well as the RIP kinases...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28353284/models-of-lrrk2-associated-parkinson-s-disease
#10
Yulan Xiong, Ted M Dawson, Valina L Dawson
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic causes of Parkinson's disease (PD) and also one of the strongest genetic risk factors in sporadic PD. The LRRK2 protein contains a GTPase and a kinase domain and several protein-protein interaction domains. Both in vitro and in vivo assays in different model systems have provided tremendous insights into the molecular mechanisms underlying LRRK2-induced dopaminergic neurodegeneration. Among all the model systems, animal models are crucial tools to study the pathogenesis of human disease...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28353282/lrrk2-and-the-immune-system
#11
Nicolas L Dzamko
Polymorphisms in leucine-rich repeat kinase 2 (LRRK2) have been linked to familial Parkinson's disease, increased risk of sporadic Parkinson's disease, increased risk of Crohn's inflammatory bowel disease, and increased susceptibility to leprosy. As well as LRRK2 mutations, these diseases share in common immune dysfunction and inflammation. LRRK2 is highly expressed in particular immune cells and has been biochemically linked to the intertwined pathways regulating inflammation, mitochondrial function, and autophagy/lysosomal function...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28353281/molecular-insights-and-functional-implication-of-lrrk2-dimerization
#12
Laura Civiero, Isabella Russo, Luigi Bubacco, Elisa Greggio
The Parkinson's disease protein leucine-rich repeat kinase 2 (LRRK2) is a multidomain protein with an enzymatic core comprising serine-threonine kinase and GTPase activities and a number of protein-protein interaction domains. While the complex domain architecture of LRRK2 has hampered its structural investigation, there is convincing evidence that LRRK2 can form dimers in solution and in the cell and that the GTPase/ROC domain plays a central role in this process. This chapter focuses on recent studies addressing the molecular nature, the functional significance, and the pathological implication of LRRK2 dimerization...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28353280/lrrk2-and-autophagy
#13
Claudia Manzoni, Patrick A Lewis
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in a wide range of cellular processes, including the catabolic pathways collectively described as autophagy. In this chapter, the evidence linking LRRK2 to autophagy will be examined, along with how regulation of autophagy and lysosomal pathways may provide a nexus between the physiological function of this protein and the different diseases with which it has been associated. Data from cellular and animal models for LRRK2 function and dysfunction support a role in the regulation and control of autophagic pathways in the cell, although the extant results do not provide a clear indication as to whether LRRK2 is a positive or negative regulator of these pathways, and there are conflicting data as to the impact of mutations in LRRK2 causative for Parkinson's disease...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28353279/understanding-the-gtpase-activity-of-lrrk2-regulation-function-and-neurotoxicity
#14
An Phu Tran Nguyen, Darren J Moore
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of Parkinson's disease (PD) with late-onset and autosomal-dominant inheritance. LRRK2 belongs to the ROCO superfamily of proteins, characterized by a Ras-of-complex (Roc) GTPase domain in tandem with a C-terminal-of-Roc (COR) domain. LRRK2 also contains a protein kinase domain adjacent to the Roc-COR tandem domain in addition to multiple repeat domains. Disease-causing familial mutations cluster within the Roc-COR tandem and kinase domains of LRRK2, where they act to either impair GTPase activity or enhance kinase activity...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28353278/lrrk2-phosphorylation
#15
R Jeremy Nichols
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene were discovered in 2004 and have been found to be the most frequently mutated gene in Parkinson's disease. LRRK2 is a large multi-domain protein with a functional GTPase and kinase domain. The signal transduction pathways in which LRRK2 is dysfunctional in the disease state are only now being resolved, but we do know that LRRK2 is, itself, a substrate of multiple kinases and phosphatases and exists in variable phosphorylated states. Autophosphorylation of LRRK2 can impact GTPase and pathological outcomes...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28338918/integrated-mirna-and-mrna-expression-profiling-reveals-the-response-regulators-of-a-susceptible-tomato-cultivar-to-early-blight-disease
#16
Deepti Sarkar, Ranjan Kumar Maji, Sayani Dey, Arijita Sarkar, Zhumur Ghosh, Pallob Kundu
Early blight, caused by the fungus Alternaria solani, is a devastating foliar disease of tomatoes, causes massive yield loss each year worldwide. Molecular basis of the compatible host-pathogen interaction was elusive. We adopted next generation sequencing approach to decipher miRNAs and mRNAs that are differentially expressed during Alternaria-stress in tomato. Some of the interesting findings were also validated by alternative techniques. Our analysis revealed 181 known-miRNAs, belonging to 121 miRNA families, of which 67 miRNAs showed at least 2-fold change in expression level with the majority being downregulated...
March 3, 2017: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
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
#17
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
#18
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
#19
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
#20
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
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