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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
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
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...
October 3, 2016: Neuroscience Bulletin
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
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
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
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 5, 2016: Oncotarget
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
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
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
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
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
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
Yeojin Bang, Kwang-Soo Kim, Wongi Seol, Hyun Jin Choi
Autosomal-dominant mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) account for the most common monogenic form of Parkinson's disease (PD). A link between autophagy dysregulation and LRRK2 has consistently been reported, but it remains poorly defined which step is targeted by LRRK2. Here, we sought to examine the effect of LRRK2 on the sequestration and degradation of aggregated protein complexes for autophagic clearance. Because two major intracellular protein degradation systems, the ubiquitin proteasome system and the autophagy, are functionally coupled, proteasome inhibition is suggested to activate autophagy...
September 2016: Molecular and Cellular Neurosciences
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
Frederick C Nucifora, Leslie G Nucifora, Chee-Hoe Ng, Nicolas Arbez, Yajuan Guo, Elaine Roby, Vered Shani, Simone Engelender, Dong Wei, Xiao-Fang Wang, Tianxia Li, Darren J Moore, Olga Pletnikova, Juan C Troncoso, Akira Sawa, Ted M Dawson, Wanli Smith, Kah-Leong Lim, Christopher A Ross
A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2. Knocking down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila model, indicating a role for endogenous WSB1 in modulating LRRK2 cell toxicity. WSB1 is in Lewy bodies in human PD post-mortem tissue...
2016: Nature Communications
Petar Podlesniy, Dolores Vilas, Peggy Taylor, Leslie M Shaw, Eduard Tolosa, Ramon Trullas
Mitochondrial DNA regulates mitochondrial function which is altered in both idiopathic and familial forms of Parkinson's disease. To investigate whether these two disease forms exhibit an altered regulation of mitochondrial DNA we measured cell free mitochondrial DNA content in cerebrospinal fluid (CSF) from idiopathic and LRRK2-related Parkinson's disease patients. The concentration of mitochondrial DNA was measured using a digital droplet polymerase chain reaction technique in a total of 98 CSF samples from a cohort of subjects including: 20 LRRK2(G2019S) mutation carriers with Parkinson's disease, 26 asymptomatic LRRK2(G2019S) mutation carriers, 31 patients with idiopathic Parkinson's disease and 21 first-degree relatives of LRRK2 Parkinson's disease patients without the mutation...
October 2016: Neurobiology of Disease
Anna Cecelia Mahne, Jonathan A Carr, Soraya Bardien, Clara Maria Schutte
BACKGROUND: Parkinson's disease (PD), with a prevalence of up to 4% in Western countries, appears to be less common in Africa, possibly in part because of genetic factors. African studies investigating the genetic causation of PD are limited. OBJECTIVE: To describe the clinical and genetic findings in a group of black South African patients with PD. METHODS: All black African patients with PD from a tertiary hospital neurology clinic were examined...
June 2016: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
Nir Giladi, Anat Mirelman, Avner Thaler, Avi Orr-Urtreger
While the phenotype of Parkinson disease (PD) is heterogeneous, treatment approaches are mostly uniform. Personalized medicine aims to treat diseases with targeted therapies based on cumulative variables, including genotype. We believe that sufficient evidence has accumulated to warrant the initiation of personalized medicine in PD based on subjects genotype and provide examples for our reasoning from observations of GBA and LRRK2 mutations carriers. While PD patients who carry the G2019S mutation in the LRRK2 gene seem to develop relatively mild disease with more frequent postural instability gait disturbance phenotype, carriers of mutations in the GBA gene tend to have an early onset, rapidly deteriorating disease, with more pronounced cognitive and autonomic impairments...
2016: Frontiers in Neurology
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