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https://www.readbyqxmd.com/read/29214211/targeted-kinase-inhibition-relieves-slowness-and-tremor-in-a-drosophila-model-of-lrrk2-parkinson-s-disease
#1
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
#2
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...
November 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29127256/development-of-phospho-specific-rab-protein-antibodies-to-monitor-in-vivo-activity-of-the-lrrk2-parkinson-s-disease-kinase
#3
Pawel Lis, Sophie Burel, Martin Steger, Matthias Mann, Fiona Brown, Federico Diez, Francesca Tonelli, Janice L Holton, Philip Winglok Ho, Shu-Leong Ho, Meng-Yun Chou, Nicole K Polinski, Terina N Martinez, Paul Davies, Dario R Alessi
Mutations that activate the LRRK2 protein kinase, predispose to Parkinson's disease, suggesting that LRRK2 inhibitors might have therapeutic benefit. Recent work has revealed that LRRK2 phosphorylates a subgroup of 14 Rab proteins, including Rab10, at a specific residue located at the centre of its effector binding Switch-II motif. In this study, we analyse the selectivity and sensitivity of polyclonal and monoclonal phospho-specific antibodies raised against 9 different LRRK2 phosphorylated Rab proteins (Rab3A/3B/3C/3D, Rab5A/5B/5C, Rab8A/8B, Rab10, Rab12, Rab29[T71], Rab29[S72], Rab35 and Rab43)...
November 10, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29038245/mitochondrial-calcium-dysregulation-contributes-to-dendrite-degeneration-mediated-by-pd-lbd-associated-lrrk2-mutants
#4
Manish Verma, Jason Callio, P Anthony Otero, Israel Sekler, Zachary P Wills, Charleen T Chu
Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs prior to the well-characterized phenotype of dendritic shortening...
October 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28649619/variable-frequency-of-lrrk2-variants-in-the-latin-american-research-consortium-on-the-genetics-of-parkinson-s-disease-large-pd-a-case-of-ancestry
#5
Mario Cornejo-Olivas, Luis Torres, Mario R Velit-Salazar, Miguel Inca-Martinez, Pilar Mazzetti, Carlos Cosentino, Federico Micheli, Claudia Perandones, Elena Dieguez, Victor Raggio, Vitor Tumas, Vanderci Borges, Henrique B Ferraz, Carlos R M Rieder, Artur Shumacher-Schuh, Carlos Velez-Pardo, Marlene Jimenez-Del-Rio, Francisco Lopera, Jorge Chang-Castello, Brennie Andreé-Munoz, Sarah Waldherr, Dora Yearout, Cyrus P Zabetian, Ignacio F Mata
Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2), primarily located in codons G2019 and R1441, represent the most common genetic cause of Parkinson's disease in European-derived populations. However, little is known about the frequency of these mutations in Latin American populations. In addition, a prior study suggested that a LRRK2 polymorphism (p.Q1111H) specific to Latino and Amerindian populations might be a risk factor for Parkinson's disease, but this finding requires replication. We screened 1734 Parkinson's disease patients and 1097 controls enrolled in the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE-PD), which includes sites in Argentina, Brazil, Colombia, Ecuador, Peru, and Uruguay...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/28576705/the-pathogenic-lrrk2-r1441c-mutation-induces-specific-deficits-modeling-the-prodromal-phase-of-parkinson-s-disease-in-the-mouse
#6
F Giesert, L Glasl, A Zimprich, L Ernst, G Piccoli, C Stautner, J Zerle, S M Hölter, D M Vogt Weisenhorn, W Wurst
The aim of the present study was to further explore the in vivo function of the Leucine-rich repeat kinase 2 (LRRK2)-gene, which is mutated in certain familial forms of Parkinson's disease (PD). We generated a mouse model harboring the disease-associated point mutation R1441C in the GTPase domain of the endogenous murine LRRK2 gene (LRRK2 R1441C line) and performed a comprehensive analysis of these animals throughout lifespan in comparison with an existing knockdown line of LRRK2 (LRRK2 knockdown line). Animals of both lines do not exhibit severe motor dysfunction or pathological signs of neurodegeneration neither at young nor old age...
September 2017: Neurobiology of Disease
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
#7
REVIEW
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/27794539/human-r1441c-lrrk2-regulates-the-synaptic-vesicle-proteome-and-phosphoproteome-in-a-drosophila-model-of-parkinson-s-disease
#8
Md Shariful Islam, Hendrik Nolte, Wright Jacob, Anna B Ziegler, Stefanie Pütz, Yael Grosjean, Karolina Szczepanowska, Aleksandra Trifunovic, Thomas Braun, Hermann Heumann, Rolf Heumann, Bernhard Hovemann, Darren J Moore, Marcus Krüger
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset, autosomal dominant familial Parkinson`s disease (PD) and variation at the LRRK2 locus contributes to the risk for idiopathic PD. LRRK2 can function as a protein kinase and mutations lead to increased kinase activity. To elucidate the pathophysiological mechanism of the R1441C mutation in the GTPase domain of LRRK2, we expressed human wild-type or R1441C LRRK2 in dopaminergic neurons of Drosophila and observe reduced locomotor activity, impaired survival and an age-dependent degeneration of dopaminergic neurons thereby creating a new PD-like model...
December 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27709685/study-of-lrrk2-variation-in-tauopathy-progressive-supranuclear-palsy-and-corticobasal-degeneration
#9
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...
January 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27521182/lrrk2-variation-and-dementia-with-lewy-bodies
#10
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
#11
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 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27314038/g2385r-and-i2020t-mutations-increase-lrrk2-gtpase-activity
#12
Dong Hwan Ho, Jihoon Jang, Eun-Hye Joe, Ilhong Son, Hyemyung Seo, Wongi Seol
The LRRK2 mutation is a major causal mutation in familial Parkinson's disease. Although LRRK2 contains functional GTPase and kinase domains and their activities are altered by pathogenic mutations, most studies focused on LRRK2 kinase activity because the most prevalent mutant, G2019S, enhances kinase activity. However, the G2019S mutation is extremely rare in the Asian population. Instead, the G2385R mutation was reported as a major risk factor in the Asian population. Similar to other LRRK2 studies, G2385R studies have also focused on kinase activity...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27111571/the-discovery-of-lrrk2-p-r1441s-a-novel-mutation-for-parkinson-s-disease-adds-to-the-complexity-of-a-mutational-hotspot
#13
Ignacio F Mata, Marie Y Davis, Alexis N Lopez, Michael O Dorschner, Erica Martinez, Dora Yearout, Brenna A Cholerton, Shu-Ching Hu, Karen L Edwards, Thomas D Bird, Cyrus P Zabetian
Mutations in the LRRK2 gene result in autosomal dominant, late onset Parkinson's disease (PD). Three such mutations (p.R1441C, p.R1441G, and p.R1441H) are known to occur within codon 1441, and haplotype analyses indicate that each one has arisen independently on multiple occasions. We sequenced the entire coding region of 18 casual genes for PD or other parkinsonian neurodegenerative disorders in the proband of a family with autosomal dominant PD. We discovered a new missense mutation in the LRRK2 gene, c.4321C>A (p...
October 2016: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
https://www.readbyqxmd.com/read/26894577/identification-of-protein-phosphatase-2a-as-an-interacting-protein-of-leucine-rich-repeat-kinase-2
#14
Panagiotis S Athanasopoulos, Wright Jacob, Sebastian Neumann, Miriam Kutsch, Dirk Wolters, Eng K Tan, Zoë Bichler, Christian Herrmann, Rolf Heumann
Mutations in the gene coding for the multi-domain protein leucine-rich repeat kinase 2 (LRRK2) are the leading cause of genetically inherited Parkinson's disease (PD). Two of the common found mutations are the R1441C and G2019S. In this study we identified protein phosphatase 2A (PP2A) as an interacting partner of LRRK2. We were able to demonstrate that the Ras of complex protein (ROC) domain is sufficient to interact with the three subunits of PP2A in human neuroblastoma SH-SY5Y cells and in HeLa cells. The alpha subunit of PP2A is interacting with LRRK2 in the perinuclear region of HeLa cells...
June 1, 2016: Biological Chemistry
https://www.readbyqxmd.com/read/26744332/lrrk2-bac-transgenic-rats-develop-progressive-l-dopa-responsive-motor-impairment-and-deficits-in-dopamine-circuit-function
#15
Max Sloan, Javier Alegre-Abarrategui, Dawid Potgieter, Anna-Kristin Kaufmann, Richard Exley, Thierry Deltheil, Sarah Threlfell, Natalie Connor-Robson, Katherine Brimblecombe, Rebecca Wallings, Milena Cioroch, David M Bannerman, J Paul Bolam, Peter J Magill, Stephanie J Cragg, Paul D Dodson, Richard Wade-Martins
Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2. To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions...
March 1, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/26622505/association-between-parkinson-s-disease-and-g2019s-and-r1441c-mutations-of-the-lrrk2-gene
#16
Xiao-Xia Li, Qin Liao, Huan Xia, Xin-Ling Yang
In recent genome-wide association studies (GWAS), 11 risk loci were identified in patients with familial and sporadic Parkinson's disease (PD) in different populations. The LRRK2 gene was found to be a mutation hot spot in European and Asian populations. The aim of the present study was to investigate the incidence of G2019S and R1441C mutations in the LRRK2 gene in individuals from the Xinjiang region of China, and to explore the associations between LRRK2 gene single nucleotide mutations and susceptibility to PD in the Uyghur and Han populations of Xinjiang...
October 2015: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/26363496/-r1441c-lrrk2-induces-the-degeneration-of-sn-dopaminergic-neurons-and-alters-the-expression-of-genes-regulating-neuronal-survival-in-a-transgenic-mouse-model
#17
Yi-Hsin Weng, Chu-Yu Chen, Kun-Jun Lin, Ying-Ling Chen, Tu-Hsueh Yeh, Ing-Tsung Hsiao, Ing-Jou Chen, Chin-Song Lu, Hung-Li Wang
Mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Several mutations in LRRK2 gene were reported in PD patients. R1441 is the second most frequent site of LRRK2 mutation. We generated (R1441C) LRRK2 transgenic mice that displayed motor deficits at the age of 16 months. Compared with wild-type mice, 16-month-old (R1441C) LRRK2 mice exhibited a significant reduction in the number of substantia nigra (SN) dopaminergic neurons...
January 2016: Experimental Neurology
https://www.readbyqxmd.com/read/26251043/pathogenic-lrrk2-mutations-through-increased-kinase-activity-produce-enlarged-lysosomes-with-reduced-degradative-capacity-and-increase-atp13a2-expression
#18
Anastasia G Henry, Soheil Aghamohammadzadeh, Harry Samaroo, Yi Chen, Kewa Mou, Elie Needle, Warren D Hirst
Lysosomal dysfunction plays a central role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease (PD). Several genes linked to genetic forms of PD, including leucine-rich repeat kinase 2 (LRRK2), functionally converge on the lysosomal system. While mutations in LRRK2 are commonly associated with autosomal-dominant PD, the physiological and pathological functions of this kinase remain poorly understood. Here, we demonstrate that LRRK2 regulates lysosome size, number and function in astrocytes, which endogenously express high levels of LRRK2...
November 1, 2015: Human Molecular Genetics
https://www.readbyqxmd.com/read/26177462/sleep-disorders-in-parkinsonian-and-nonparkinsonian-lrrk2-mutation-carriers
#19
Claustre Pont-Sunyer, Alex Iranzo, Carles Gaig, Ana Fernández-Arcos, Dolores Vilas, Francesc Valldeoriola, Yaroslau Compta, Ruben Fernández-Santiago, Manel Fernández, Angels Bayés, Matilde Calopa, Pilar Casquero, Oriol de Fàbregues, Serge Jaumà, Victor Puente, Manel Salamero, Maria José Martí, Joan Santamaría, Eduard Tolosa
OBJECTIVE: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). METHODS: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD...
2015: PloS One
https://www.readbyqxmd.com/read/25939886/lrrk2-dephosphorylation-increases-its-ubiquitination
#20
Jing Zhao, Tyler P Molitor, J William Langston, R Jeremy Nichols
Activating mutations in the leucine rich repeat protein kinase 2 (LRRK2) gene are the most common cause of inherited Parkinson's disease (PD). LRRK2 is phosphorylated on a cluster of phosphosites including Ser(910), Ser(935), Ser(955) and Ser(973), which are dephosphorylated in several PD-related LRRK2 mutants (N1437H, R1441C/G, Y1699C and I2020T) linking the regulation of these sites to PD. These serine residues are also dephosphorylated after kinase inhibition and lose 14-3-3 binding, which serves as a pharmacodynamic marker for inhibited LRRK2...
July 1, 2015: Biochemical Journal
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