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https://www.readbyqxmd.com/read/28487191/human-lrrk2-g2019s-mutation-represses-post-synaptic-protein-psd95-and-causes-cognitive-impairment-in-transgenic-mice
#1
Samuel O Adeosun, Xu Hou, Baoying Zheng, Heather L Melrose, Thomas Mosley, Jun Ming Wang
BACKGROUND: LRRK2 G2019S mutation is associated with increased kinase activity and is the most common mutation associated with late-onset PD. However, the transgenic mouse model has not recapitulated cardinal PD-related motor phenotypes. Non-motor symptoms of PD including cognitive impairments are very common and may appear earlier than the motor symptoms. The objective of this study was to determine whether human LRRK2 with G2019S mutation causes hippocampus-dependent cognitive deficits in mice Results Male (LRRK2-G2019S) LRRK2-Tg mice showed impairments in the early portion of the Two-day radial arm water maze acquisition trial as well as in the reversal learning on the third day...
May 6, 2017: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/28465860/lrrk2-g2019s-mutation-prevalence-and-clinical-features-in-moroccans-with-parkinson-s-disease
#2
Ahmed Bouhouche, Houyam Tibar, Rafiqua Ben El Haj, Khalil El Bayad, Rachid Razine, Sanaa Tazrout, Asmae Skalli, Naima Bouslam, Loubna Elouardi, Ali Benomar, Mohammed Yahyaoui, Wafa Regragui
Background. The LRRK2 G2019S mutation is the most common genetic determinant of Parkinson's disease (PD) identified to date. This mutation, reported in both familial and sporadic PD, occurs at elevated frequencies in Maghreb population. In the present study, we examined the prevalence of the G2019S mutation in the Moroccan population and we compared the motor and nonmotor phenotype of G2019S carriers to patients with idiopathic Parkinson's disease. Methods. 100 PD patients were assessed for motor and nonmotor symptoms, current medication, and motor complication including motor fluctuations and dyskinesia...
2017: Parkinson's Disease
https://www.readbyqxmd.com/read/28420983/increased-oxidative-stress-markers-in-cerebrospinal-fluid-from-healthy-subjects-with-parkinson-s-disease-associated-lrrk2-gene-mutations
#3
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/28406934/dat-spect-assessment-depicts-dopamine-depletion-among-asymptomatic-g2019s-lrrk2-mutation-carriers
#4
COMPARATIVE STUDY
Moran Artzi, Einat Even-Sapir, Hedva Lerman Shacham, Avner Thaler, Avi Orr Urterger, Susan Bressman, Karen Marder, Talma Hendler, Nir Giladi, Dafna Ben Bashat, Anat Mirelman
Identification of early changes in Dopamine-Transporter (DaT) SPECT imaging expected in the prodromal phase of Parkinson's disease (PD), are usually overlooked. Carriers of the G2019S LRRK2 mutation are known to be at high risk for developing PD, compared to non-carriers. In this work we aimed to study early changes in Dopamine uptake in non-manifesting PD carriers (NMC) of the G2019S LRRK2 mutation using quantitative DaT-SPECT analysis and to examine the potential for early prediction of PD. Eighty Ashkenazi-Jewish subjects were included in this study: eighteen patients with PD; thirty-one NMC and thirty-one non-manifesting non-carriers (NMNC)...
2017: PloS One
https://www.readbyqxmd.com/read/28370517/the-prodromal-phase-of-leucine-rich-repeat-kinase-2-associated-parkinson-disease-clinical-and-imaging-studies
#5
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/28353279/understanding-the-gtpase-activity-of-lrrk2-regulation-function-and-neurotoxicity
#6
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/28353276/leucine-rich-repeat-kinase-lrrk2-genetics-and-parkinson-s-disease
#7
Edoardo Monfrini, Alessio Di Fonzo
The discovery of LRRK2 mutations as a cause of Parkinson's disease (PD), including the sporadic late-onset form, established the decisive role of genetics in the field of PD research. Among LRRK2 mutations, the G2019S, mostly lying in a haplotype originating from a common Middle Eastern ancestor, has been identified in different populations worldwide. The G2385R and R1628P variants represent validated risk factors for PD in Asian populations. Here, we describe in detail the origin, the present worldwide epidemiology, and the penetrance of LRRK2 mutations...
2017: Advances in Neurobiology
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
#8
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/28292328/age-dependent-dopamine-transporter-dysfunction-and-serine129-phospho-%C3%AE-synuclein-overload-in-g2019s-lrrk2-mice
#9
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/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 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 affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis...
April 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28186666/impaired-intracortical-transmission-in-g2019s-leucine-rich-repeat-kinase-parkinson-patients
#12
Viviana Ponzo, Francesco Di Lorenzo, Livia Brusa, Tommaso Schirinzi, Stefania Battistini, Claudia Ricci, Manolo Sambucci, Carlo Caltagirone, Giacomo Koch
OBJECTIVES: A mutation in leucine-rich repeat kinase 2 is the most common cause of hereditary Parkinson's disease (PD), yet the neural mechanisms and the circuitry potentially involved are poorly understood. METHODS: We used different transcranial magnetic stimulation protocols to explore in the primary motor cortex the activity of intracortical circuits and cortical plasticity (long-term potentiation) in patients with the G2019S leucine-rich repeat kinase 2 gene mutation when compared with idiopathic PD patients and age-matched healthy subjects...
February 10, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28131193/the-heterozygous-r1441c-mutation-of-leucine-rich-repeat-kinase-2-gene-in-a-chinese-patient-with-parkinson-disease-a-five-year-follow-up-and-literatures-review
#13
Fang Peng, Yi-Min Sun, Chen Chen, Su-Shan Luo, Da-Ke Li, Yi-Xuan Wang, Ke Yang, Feng-Tao Liu, Chuan-Tao Zuo, Zheng-Tong Ding, Yu An, Jian-Jun Wu, Jian Wang
BACKGROUND: Leucine-rich repeat kinase 2 gene (LRRK2) was recognized associated with both familial and sporadic Parkinson Disease (PD). Seven missense mutations (G2019S, R1441C, R1441G, R1441H, Y1699C, I2020T, N1437H) of it have been confirmed disease- causing. They were common among Caucasian PD patients, but rarely reported in Asian, especially in Chinese Han population. OBJECTIVES: We aimed to identify the frequencies of these seven mutations of LRRK2 in Chinese early-onset PD (EOPD) patients and analyze the phenotypes...
February 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28096185/transcriptomic-profiling-of-purified-patient-derived-dopamine-neurons-identifies-convergent-perturbations-and-therapeutics-for-parkinson-s-disease
#14
Cynthia Sandor, Paul Robertson, Charmaine Lang, Andreas Heger, Heather Booth, Jane Vowles, Lorna Witty, Rory Bowden, Michele Hu, Sally A Cowley, Richard Wade-Martins, Caleb Webber
While induced pluripotent stem cell (iPSC) technologies enable the study of inaccessible patient cell types, cellular heterogeneity can confound the comparison of gene expression profiles between iPSC-derived cell lines. Here, we purified iPSC-derived human dopaminergic neurons (DaNs) using the intracellular marker, tyrosine hydroxylase. Once purified, the transcriptomic profiles of iPSC-derived DaNs appear remarkably similar to profiles obtained from mature post-mortem DaNs. Comparison of the profiles of purified iPSC-derived DaNs derived from Parkinson's disease (PD) patients carrying LRRK2 G2019S variants to controls identified significant functional convergence amongst differentially-expressed (DE) genes...
February 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28090684/predict-pd-an-online-approach-to-prospectively-identify-risk-indicators-of-parkinson-s-disease
#15
Alastair J Noyce, Lea R'Bibo, Luisa Peress, Jonathan P Bestwick, Kerala L Adams-Carr, Niccolo E Mencacci, Christopher H Hawkes, Joseph M Masters, Nicholas Wood, John Hardy, Gavin Giovannoni, Andrew J Lees, Anette Schrag
BACKGROUND: A number of early features can precede the diagnosis of Parkinson's disease (PD). OBJECTIVE: To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population. METHODS: Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations...
February 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27939437/the-dual-enzyme-lrrk2-hydrolyzes-gtp-in-both-its-gtpase-and-kinase-domains-in-vitro
#16
Zhiyong Liu, Andrew B West
The evolutionarily conserved enzyme encoded by the leucine-rich repeat kinase 2 gene, LRRK2, harbors both a Rab-like GTPase domain and a serine/threonine protein kinase domain. Pathogenic mutations in either the GTPase or kinase domain can cause neurodegeneration and Parkinson disease. No high-resolution structure of the human LRRK2 kinase domain is available but the most common mutation, G2019S in the kinase domain, is predicted to alter the ATP-binding pocket structure and interaction with divalent cations...
March 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27914807/phosphorylation-of-p53-by-lrrk2-induces-microglial-tumor-necrosis-factor-%C3%AE-mediated-neurotoxicity
#17
Dong Hwan Ho, Wongi Seol, Jin Hwan Eun, Il-Hong Son
Leucine-rich repeat kinase (LRRK2), a major causal gene of Parkinson's disease (PD), functions as a kinase. The most prevalent mutation of LRRK2 is G2019S. It exhibits increased kinase activity compared to the wildtype LRRK2. Previous studies have shown that LRRK2 can phosphorylate p53 at T304 and T377 of threonine-X-arginine (TXR) motif in neurons. Reduction of LRRK2 expression or inhibition of LRRK2 kinase activity has been shown to be able to alleviate LPS-induced neuroinflammation in microglia cells. In this study, we found that LRRK2 could also phosphorylate p53 in microglia model BV2 cells...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27898095/efficient-generation-of-orthologous-point-mutations-in-pigs-via-crispr-assisted-ssodn-mediated-homology-directed-repair
#18
Kankan Wang, Xiaochun Tang, Yan Liu, Zicong Xie, Xiaodong Zou, Mengjing Li, Hongming Yuan, Hongsheng Ouyang, Huping Jiao, Daxin Pang
Precise genome editing in livestock is of great value for the fundamental investigation of disease modeling. However, genetically modified pigs carrying subtle point mutations were still seldom reported despite the rapid development of programmable endonucleases. Here, we attempt to investigate single-stranded oligonucleotides (ssODN) mediated knockin by introducing two orthologous pathogenic mutations, p.E693G for Alzheimer's disease and p.G2019S for Parkinson's disease, into porcine APP and LRRK2 loci, respectively...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27863501/mutations-in-lrrk2-impair-nf-%C3%AE%C2%BAb-pathway-in-ipsc-derived-neurons
#19
Rakel López de Maturana, Valérie Lang, Amaia Zubiarrain, Amaya Sousa, Nerea Vázquez, Ana Gorostidi, Julio Águila, Adolfo López de Munain, Manuel Rodríguez, Rosario Sánchez-Pernaute
BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both familial and idiopathic forms of Parkinson's disease (PD). Neuroinflammation is a key event in neurodegeneration and aging, and there is mounting evidence of LRRK2 involvement in inflammatory pathways. In a previous study, we described an alteration of the inflammatory response in dermal fibroblasts from PD patients expressing the G2019S and R1441G mutations in LRRK2. METHODS: Taking advantage of cellular reprogramming, we generated induced pluripotent stem cell (iPSC) lines and neurons thereafter, harboring LRRK2(G2019S) and LRRK2(R1441G) mutations...
November 18, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27832104/activation-of-fadd-dependent-neuronal-death-pathways-as-a-predictor-of-pathogenicity-for-lrrk2-mutations
#20
Katerina Melachroinou, Emmanouela Leandrou, Polytimi-Eleni Valkimadi, Anna Memou, Georgios Hadjigeorgiou, Leonidas Stefanis, Hardy J Rideout
BACKGROUND: Despite the plethora of sequence variants in LRRK2, only a few clearly segregate with PD. Even within this group of pathogenic mutations, the phenotypic profile can differ widely. OBJECTIVE: We examined multiple properties of LRRK2 behavior in cellular models over-expressing three sequence variants described in Greek PD patients in comparison to several known pathogenic and non-pathogenic LRRK2 mutations, to determine if specific phenotypes associated with pathogenic LRRK2 can be observed in other less-common sequence variants for which pathogenicity is unclear based on clinical and/or genetic data alone...
2016: PloS One
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