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https://www.readbyqxmd.com/read/27898095/efficient-generation-of-orthologous-point-mutations-in-pigs-via-crispr-assisted-ssodn-mediated-homology-directed-repair
#1
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
#2
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
#3
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
https://www.readbyqxmd.com/read/27812199/leucine-rich-repeat-kinase-2-influences-fate-decision-of-human-monocytes-differentiated-from-induced-pluripotent-stem-cells
#4
Anna Speidel, Sandra Felk, Peter Reinhardt, Jared Sterneckert, Frank Gillardon
Mutations in Leucine-rich repeat kinase 2 (LRRK2) are strongly associated with familial Parkinson's disease (PD). High expression levels in immune cells suggest a role of LRRK2 in regulating the immune system. In this study, we investigated the effect of the LRRK2 (G2019S) mutation in monocytes, using a human stem cell-derived model expressing LRRK2 at endogenous levels. We discovered alterations in the differentiation pattern of LRRK2 mutant, compared to non-mutant isogenic controls, leading to accelerated monocyte production and a reduction in the non-classical CD14+CD16+ monocyte subpopulation in the LRRK2 mutant cells...
2016: PloS One
https://www.readbyqxmd.com/read/27798102/additional-rare-variant-analysis-in-parkinson-s-disease-cases-with-and-without-known-pathogenic-mutations-evidence-for-oligogenic-inheritance
#5
Steven J Lubbe, Valentina Escott-Price, J Raphael Gibbs, Mike A Nalls, Jose Bras, T Ryan Price, Aude Nicolas, Iris E Jansen, Kin Y Mok, Alan M Pittman, James E Tomkins, Patrick A Lewis, Alastair J Noyce, Suzanne Lesage, Manu Sharma, Elena R Schiff, Adam P Levine, Alexis Brice, Thomas Gasser, John Hardy, Peter Heutink, Nicholas W Wood, Andrew B Singleton, Nigel M Williams, Huw R Morris
Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognized primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis...
October 18, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27777137/autosomal-dominant-parkinson-s-disease-incidence-of-mutations-in-lrrk2-snca-vps35-and-gba-genes-in-brazil
#6
Gabriella de M Abreu, Débora Cristina T Valença, Mário Campos, Camilla P da Silva, João S Pereira, Marco A Araujo Leite, Ana Lucia Rosso, Denise H Nicaretta, Luiz Felipe R Vasconcellos, Delson José da Silva, Marcus V Della Coletta, Jussara M Dos Santos, Andressa P Gonçalves, Cíntia B Santos-Rebouças, Márcia M G Pimentel
INTRODUCTION: Amongst Parkinson's disease (PD) genetic factors, mutations in LRRK2, SNCA, VPS35 and GBA genes are recognized causes of PD. Nonetheless, few genetic screenings have been conducted in families with a history of PD consistent with autosomal dominant inheritance (ADPD), and their relevance to the etiology of PD has been poorly explored in Latin American populations, such as the Brazilian one, with a high degree of admixture. METHODS: In order to assess the contribution of specific mutations in LRRK2, SNCA, VPS35 and GBA genes to ADPD in Brazil, we conducted the first molecular evaluation in a cohort of 141 index cases from families with ADPD...
December 2, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27723861/high-frequency-of-gba-gene-mutations-in-dementia-with-lewy-bodies-among-ashkenazi-jews
#7
Tamara Shiner, Anat Mirelman, Mali Gana Weisz, Anat Bar-Shira, Elissa Ash, Ron Cialic, Naomi Nevler, Tanya Gurevich, Noa Bregman, Avi Orr-Urtreger, Nir Giladi
Importance: Mutations in the glucocerebrosidase (GBA) gene are a risk factor for the development of dementia with Lewy bodies (DLB). These mutations are common among Ashkenazi Jews (AJ) and appear to have an effect on the natural history of the disease. Objectives: To evaluate the clinical and genetic characteristics of an AJ cohort of patients diagnosed with DLB, assess the association of phenotype of DLB with GBA mutations, and explore the effects of these mutations on the clinical course of the disease...
October 10, 2016: JAMA Neurology
https://www.readbyqxmd.com/read/27709685/study-of-lrrk2-variation-in-tauopathy-progressive-supranuclear-palsy-and-corticobasal-degeneration
#8
Monica Sanchez-Contreras, Michael G Heckman, Pawel Tacik, Nancy Diehl, Patricia H Brown, Alexandra I Soto-Ortolaza, Elizabeth A Christopher, Ronald L Walton, Owen A Ross, Lawrence I Golbe, Neill Graff-Radford, Zbigniew K Wszolek, Dennis W Dickson, Rosa Rademakers
BACKGROUND: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers. METHODS: To estimate the frequency of pathogenic LRRK2 mutations and to evaluate the association of common LRRK2 variants with risk of primary tauopathies, we studied 1039 progressive supranuclear palsy (PSP) and 145 corticobasal degeneration patients from the Mayo Clinic Florida brain bank and 1790 controls ascertained at Mayo Clinic...
October 6, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27699718/olfactory-dysfunction-in-parkinson-s-disease-patients-with-the-lrrk2-g2385r-variant
#9
Ming Cao, Zhu-Qin Gu, Yuan Li, Hui Zhang, Xiao-Juan Dan, Shan-Shan Cen, Da-Wei Li, Piu Chan
Olfactory dysfunction has been reported in Parkinson's disease (PD) patients carrying the LRRK2 G2019S variant in Caucasians but rarely in those with the LRRK2 G2385R variant. In this study, we performed genotyping for the LRRK2 G2385R variant in PD patients recruited from the Movement Disorder Clinic of Xuanwu Hospital in Beijing and in healthy controls randomly selected from the Beijing Longitudinal Study on Aging cohort. The "five-odor olfactory detection array", an olfactory threshold test, was used to assess olfactory function...
December 2016: Neuroscience Bulletin
https://www.readbyqxmd.com/read/27658356/pharmacological-lrrk2-kinase-inhibition-induces-lrrk2-protein-destabilization-and-proteasomal-degradation
#10
E Lobbestael, L Civiero, T De Wit, J-M Taymans, E Greggio, V Baekelandt
Leucine-rich repeat kinase 2 (LRRK2) kinase activity is increased in several pathogenic mutations, including the most common mutation, G2019S, and is known to play a role in Parkinson's disease (PD) pathobiology. This has stimulated the development of potent, selective LRRK2 kinase inhibitors as one of the most prevailing disease-modifying therapeutic PD strategies. Although several lines of evidence support beneficial effects of LRRK2 kinase inhibitors, many questions need to be answered before clinical applications can be envisaged...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27640816/dopaminergic-neurons-differentiating-from-lrrk2-g2019s-induced-pluripotent-stem-cells-show-early-neuritic-branching-defects
#11
Laurence Borgs, Elise Peyre, Philippe Alix, Kevin Hanon, Benjamin Grobarczyk, Juliette D Godin, Audrey Purnelle, Nathalie Krusy, Pierre Maquet, Philippe Lefebvre, Vincent Seutin, Brigitte Malgrange, Laurent Nguyen
Some mutations of the LRRK2 gene underlie autosomal dominant form of Parkinson's disease (PD). The G2019S is a common mutation that accounts for about 2% of PD cases. To understand the pathophysiology of this mutation and its possible developmental implications, we developed an in vitro assay to model PD with human induced pluripotent stem cells (hiPSCs) reprogrammed from skin fibroblasts of PD patients suffering from the LRKK2 G2019S mutation. We differentiated the hiPSCs into neural stem cells (NSCs) and further into dopaminergic neurons...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27613114/genetic-causes-of-parkinson-s-disease-in-the-maltese-a-study-of-selected-mutations-in-lrrk2-mthfr-qdpr-and-spr
#12
Charmaine Zahra, Christine Tabone, Graziella Camilleri, Alex E Felice, Rosienne Farrugia, Stephanie Bezzina Wettinger
BACKGROUND: Mutations in Leucine-rich repeat kinase 2 NM_198578 (LRRK2 c.6055G > A (p.G2019S), LRRK2 c.4321C > G (p.R1441G)) and alpha-synuclein NM_000345 (SNCA c.209G > A (p.A53T)) genes causing Parkinson's disease (PD) are common in Mediterranean populations. Variants in the Quinoid Dihydropteridine Reductase NM_000320 (QDPR c.68G > A (p.G23D)), Sepiapterin Reductase NM_003124 (SPR c.596-2A > G) and Methylenetetrahydrofolate Reductase NM_005957 (MTHFR c...
2016: BMC Medical Genetics
https://www.readbyqxmd.com/read/27521182/lrrk2-variation-and-dementia-with-lewy-bodies
#13
Michael G Heckman, Alexandra I Soto-Ortolaza, Monica Y Sanchez Contreras, Melissa E Murray, Otto Pedraza, Nancy N Diehl, Ronald Walton, Catherine Labbé, Oswaldo Lorenzo-Betancor, Ryan J Uitti, Jay van Gerpen, Nilüfer Ertekin-Taner, Glenn E Smith, Kejal Kantarci, Rodolfo Savica, David T Jones, Jonathan Graff-Radford, David S Knopman, Val J Lowe, Clifford R Jack, Ronald C Petersen, Joseph E Parisi, Rosa Rademakers, Zbigniew K Wszolek, Neill R Graff-Radford, Tanis J Ferman, Dennis W Dickson, Bradley F Boeve, Owen A Ross
INTRODUCTION: The leucine-rich repeat kinase 2 (LRRK2) gene contains several variants that cause Parkinson's disease (PD) and others that modify PD risk. However, little is known about the role of LRRK2 in dementia with Lewy bodies (DLB). Aims of this study were to screen DLB patients for pathogenic LRRK2 variants and to evaluate associations between common LRRK2 variants and risk of DLB. METHODS: 417 clinical DLB patients and 1790 controls were included in the primary analysis...
October 2016: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/27509057/increased-rab35-expression-is-a-potential-biomarker-and-implicated-in-the-pathogenesis-of-parkinson-s-disease
#14
Ching-Chi Chiu, Tu-Hsueh Yeh, Szu-Chia Lai, Yi-Hsin Weng, Yin-Cheng Huang, Yi-Chuan Cheng, Rou-Shayn Chen, Ying-Zu Huang, June Hung, Chiung-Chu Chen, Wey-Yil Lin, Hsiu-Chen Chang, Yu-Jie Chen, Chao-Lang Chen, Hsin-Yi Chen, Yan-Wei Lin, Yah-Huei Wu-Chou, Hung-Li Wang, Chin-Song Lu
Parkinson's disease (PD) is the second common neurodegenerative disease. Identification of biomarkers for early diagnosis and prediction of disease progression is important. The present comparative proteomic study of serum samples using two-dimensional fluorescence differential gel electrophoresis followed by ELISA confirmation demonstrated that protein expression of Rab35 was increased in PD patients compared with matched control subjects and other parkinsonian disorders, progressive supranuclear palsy (PSP) and multiple system atrophy (MSA)...
August 5, 2016: Oncotarget
https://www.readbyqxmd.com/read/27474410/phos-tag-analysis-of-rab10-phosphorylation-by-lrrk2-a-powerful-assay-for-assessing-kinase-function-and-inhibitors
#15
Genta Ito, Kristina Katsemonova, Francesca Tonelli, Pawel Lis, Marco A S Baptista, Natalia Shpiro, Graham Duddy, Steve Wilson, Philip Wing-Lok Ho, Shu-Leong Ho, Alastair D Reith, Dario R Alessi
Autosomal dominant mutations that activate the leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson's disease. Recent work has revealed that LRRK2 directly phosphorylates a conserved threonine/serine residue in the effector-binding switch-II motif of a number of Rab GTPase proteins, including Rab10. Here we describe a facile and robust method to assess phosphorylation of endogenous Rab10 in mouse embryonic fibroblasts (MEFs), lung and spleen-derived B-cells, based on the ability of the Phos-tag reagent to retard the electrophoretic mobility of LRRK2-phosphorylated Rab10...
September 1, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27430880/arm-swing-as-a-potential-new-prodromal-marker-of-parkinson-s-disease
#16
Anat Mirelman, Hagar Bernad-Elazari, Avner Thaler, Eytan Giladi-Yacobi, Tanya Gurevich, Mali Gana-Weisz, Rachel Saunders-Pullman, Deborah Raymond, Nancy Doan, Susan B Bressman, Karen S Marder, Roy N Alcalay, Ashwini K Rao, Daniela Berg, Kathrin Brockmann, Jan Aasly, Bjørg Johanne Waro, Eduardo Tolosa, Dolores Vilas, Claustre Pont-Sunyer, Avi Orr-Urtreger, Jeffrey M Hausdorff, Nir Giladi
BACKGROUND: Reduced arm swing is a well-known clinical feature of Parkinson's disease (PD), often observed early in the course of the disease. We hypothesized that subtle changes in arm swing and axial rotation may also be detectable in the prodromal phase. OBJECTIVE: The purpose of this study was to evaluate the relationship between the LRRK2-G2019S mutation, arm swing, and axial rotation in healthy nonmanifesting carriers and noncarriers of the G2019S mutation and in patients with PD...
July 19, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27423549/functional-properties-of-lrrk2-mutations-in-taiwanese-parkinson-disease
#17
Kuo-Hsuan Chang, Chiung-Mei Chen, Chih-Hsin Lin, Wen-Teng Chang, Pei-Ru Jiang, Ya-Chin Hsiao, Yih-Ru Wu, Guey-Jen Lee-Chen
BACKGROUND/PURPOSE: Leucine-rich repeat kinase 2 (LRRK2) is a large protein encoding multiple functional domains. Mutations within different LRRK2 domains have been considered to be involved in the development of Parkinson disease by different mechanisms. Our previous study found three LRRK2 mutations-p.R767H, p.S885N, and p.R1441H-in Taiwanese patients with Parkinson disease. METHODS: We evaluated the functional properties of LRRK2 p.R767H, p.S885N, and p.R1441H mutations by overexpressing them in human embryonic kidney 293 and neuroblastoma SK-N-SH cells...
July 13, 2016: Journal of the Formosan Medical Association, Taiwan Yi Zhi
https://www.readbyqxmd.com/read/27413152/g2019s-lrrk2-expression-augments-%C3%AE-synuclein-sequestration-into-inclusions-in-neurons
#18
Laura A Volpicelli-Daley, Hisham Abdelmotilib, Zhiyong Liu, Lindsay Stoyka, João Paulo Lima Daher, Austen J Milnerwood, Vivek K Unni, Warren D Hirst, Zhenyu Yue, Hien T Zhao, Kyle Fraser, Richard E Kennedy, Andrew B West
UNLABELLED: Pathologic inclusions define α-synucleinopathies that include Parkinson's disease (PD). The most common genetic cause of PD is the G2019S LRRK2 mutation that upregulates LRRK2 kinase activity. However, the interaction between α-synuclein, LRRK2, and the formation of α-synuclein inclusions remains unclear. Here, we show that G2019S-LRRK2 expression, in both cultured neurons and dopaminergic neurons in the rat substantia nigra pars compact, increases the recruitment of endogenous α-synuclein into inclusions in response to α-synuclein fibril exposure...
July 13, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27393345/genome-wide-assessment-of-parkinson-s-disease-in-a-southern-spanish-population
#19
Sara Bandrés-Ciga, Timothy Ryan Price, Francisco Javier Barrero, Francisco Escamilla-Sevilla, Javier Pelegrina, Sampath Arepalli, Dena Hernández, Blanca Gutiérrez, Jorge Cervilla, Margarita Rivera, Alberto Rivera, Jing-Hui Ding, Francisco Vives, Michael Nalls, Andrew Singleton, Raquel Durán
Here, we set out to study the genetic architecture of Parkinson's disease (PD) through a Genome-Wide Association Study in a Southern Spanish population. About 240 PD cases and 192 controls were genotyped on the NeuroX array. We estimated genetic variation associated with PD risk and age at onset (AAO). Risk profile analyses for PD and AAO were performed using a weighted genetic risk score. Total heritability was estimated by genome-wide complex trait analysis. Rare variants were screened with single-variant and burden tests...
September 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/27383589/altered-development-of-synapse-structure-and-function-in-striatum-caused-by-parkinson-s-disease-linked-lrrk2-g2019s-mutation
#20
Bridget A Matikainen-Ankney, Nebojsa Kezunovic, Roxana E Mesias, Yuan Tian, Frances M Williams, George W Huntley, Deanna L Benson
UNLABELLED: Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) can cause Parkinson's disease (PD), and the most common disease-associated mutation, G2019S, increases kinase activity. Because LRRK2 expression levels rise during synaptogenesis and are highest in dorsal striatal spiny projection neurons (SPNs), we tested the hypothesis that the LRRK2-G2019S mutation would alter development of excitatory synaptic networks in dorsal striatum. To circumvent experimental confounds associated with LRRK2 overexpression, we used mice expressing LRRK2-G2019S or D2017A (kinase-dead) knockin mutations...
July 6, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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