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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
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...
October 29, 2016: Human Molecular Genetics
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
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
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
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
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
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
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
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
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
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
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
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
William M Johnson, Chen Yao, Sandra L Siedlak, Wenzhang Wang, Xiongwei Zhu, Guy A Caldwell, Amy L Wilson-Delfosse, John J Mieyal, Shu G Chen
Parkinson's disease (PD) is characterized by selective degeneration of dopaminergic neurons. Although the etiology of PD remains incompletely understood, oxidative stress has been implicated as an important contributor in the development of PD. Oxidative stress can lead to oxidation and functional perturbation of proteins critical to neuronal survival. Glutaredoxin 1 (Grx1) is an evolutionally conserved antioxidant enzyme that repairs protein oxidation by reversing the oxidative modification of cysteine known as S-glutathionylation...
March 1, 2015: Human Molecular Genetics
Vinay K Godena, Nicholas Brookes-Hocking, Annekathrin Moller, Gary Shaw, Matthew Oswald, Rosa M Sancho, Christopher C J Miller, Alexander J Whitworth, Kurt J De Vos
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo...
October 15, 2014: Nature Communications
Hyun Jin Cho, Jia Yu, Chengsong Xie, Parvathi Rudrabhatla, Xi Chen, Junbing Wu, Loukia Parisiadou, Guoxiang Liu, Lixin Sun, Bo Ma, Jinhui Ding, Zhihua Liu, Huaibin Cai
Leucine-rich repeat kinase 2 (LRRK2) has been associated with Parkinson's disease (PD) and other disorders. However, its normal physiological functions and pathogenic properties remain elusive. Here we show that LRRK2 regulates the anterograde ER-Golgi transport through anchoring Sec16A at the endoplasmic reticulum exit sites (ERES). LRRK2 interacted and co-localized with Sec16A, a key protein in the formation of ERES. Lrrk2 depletion caused a dispersion of Sec16A from ERES and impaired ER export. In neurons, LRRK2 and Sec16A showed extensive co-localization at the dendritic ERES (dERES) that locally regulate the transport of proteins to the dendritic spines...
October 16, 2014: EMBO Journal
Elpida Tsika, Meghna Kannan, Caroline Shi-Yan Foo, Dustin Dikeman, Liliane Glauser, Sandra Gellhaar, Dagmar Galter, Graham W Knott, Ted M Dawson, Valina L Dawson, Darren J Moore
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). The clinical and neurochemical features of LRRK2-linked PD are similar to idiopathic disease although neuropathology is somewhat heterogeneous. Dominant mutations in LRRK2 precipitate neurodegeneration through a toxic gain-of-function mechanism which can be modeled in transgenic mice overexpressing human LRRK2 variants. A number of LRRK2 transgenic mouse models have been developed that display abnormalities in dopaminergic neurotransmission and alterations in tau metabolism yet without consistently inducing dopaminergic neurodegeneration...
November 2014: Neurobiology of Disease
Chia-Lung Chuang, Yu-Ning Lu, Hung-Cheng Wang, Hui-Yun Chang
Leucine-rich repeat kinase 2 (LRRK2) is a complex kinase and mutations in LRRK2 are perhaps the most common genetic cause of Parkinson's disease (PD). However, the identification of the normal physiological function of LRRK2 remains elusive. Here, we show that LRRK2 protects neurons against apoptosis induced by the Drosophila genes grim, hid and reaper. Genetic dissection reveals that Akt is the critical downstream kinase of LRRK2 that phosphorylates and inhibits FOXO1, and thereby promotes survival. Like human LRRK2, Drosophila lrrk also promotes neuron survival; lrrk loss-of-function mutant displays reduced cell numbers, which can be rescued by LRRK2 expression...
November 1, 2014: Human Molecular Genetics
Edward D Plowey, Jon W Johnson, Erin Steer, Wan Zhu, David A Eisenberg, Natalie M Valentino, Yong-Jian Liu, Charleen T Chu
Mutations in leucine-rich repeat kinase 2 (LRRK2), which are associated with autosomal dominant Parkinson's disease, elicit progressive dendrite degeneration in neurons. We hypothesized that synaptic dysregulation contributes to mutant LRRK2-induced dendritic injury. We performed in vitro whole-cell voltage clamp studies of glutamatergic receptor agonist responses and glutamatergic synaptic activity in cultured rat cortical neurons expressing full-length wild-type and mutant forms of LRRK2. Expression of the pathogenic G2019S or R1441C LRRK2 mutants resulted in larger whole-cell current responses to direct application of AMPA and NMDA receptor agonists...
September 2014: Biochimica et Biophysica Acta
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