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https://www.readbyqxmd.com/read/28102045/inflammatory-profile-discriminates-clinical-subtypes-in-lrrk2-associated-parkinson-s-disease
#1
K Brockmann, C Schulte, N Schneiderhan-Marra, A Apel, C Pont-Sunyer, D Vilas, J Ruiz-Martinez, M Langkamp, J-C Corvol, F Cormier, T Knorpp, T O Joos, A Bernard, T Gasser, C Marras, B Schüle, J O Aasly, T Foroud, J F Marti-Masso, A Brice, E Tolosa, D Berg, W Maetzler
BACKGROUND AND PURPOSE: The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PDLRRK2 ) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes. METHODS: An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PDLRRK2 patients from the MJFF LRRK2 Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor...
February 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/28099919/autophagy-related-gene-lrrk2-is-likely-a-susceptibility-gene-for-systemic-lupus-erythematosus-in-northern-han-chinese
#2
Yue-Miao Zhang, Xu-Jie Zhou, Fa-Juan Cheng, Yuan-Yuan Qi, Ping Hou, Ming-Hui Zhao, Hong Zhang
Autophagy is associated with various immune diseases, including systemic lupus erythematosus (SLE). Seven variants within autophagy-related genes previously reported to show top association signals by genome-wide association studies in immune diseases were selected for analysis. Initially, 510 SLE patients (631 controls) were enrolled in the study. An additional independent cohort of 511 SLE patients (687 controls) was included for replication. Polymorphism rs2638272 in LRRK2 gene showed significant association with susceptibility to SLE (P = 1...
January 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28098219/combined-lrrk2-mutation-aging-and-chronic-low-dose-oral-rotenone-as-a-model-of-parkinson-s-disease
#3
Hui-Fang Liu, Philip Wing-Lok Ho, Gideon Chi-Ting Leung, Colin Siu-Chi Lam, Shirley Yin-Yu Pang, Lingfei Li, Michelle Hiu-Wai Kung, David Boyer Ramsden, Shu-Leong Ho
Aging, genetics and environmental toxicity are important etiological factors in Parkinson's disease (PD). However, its pathogenesis remains unclear. A major obstacle is the lack of an appropriate experimental model which incorporates genetic susceptibility, aging and prolonged environmental toxicity. Here, we explored the interplay amongst these factors using mutant LRRK2(R1441G) (leucine-rich-repeat-kinase-2) knockin mice. We found that mutant primary cortical and mesencephalic dopaminergic neurons were more susceptible to rotenone-induced ATP deficiency and cell death...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28096185/transcriptomic-profiling-of-purified-patient-derived-dopamine-neurons-identifies-convergent-perturbations-and-therapeutics-for-parkinson-s-disease
#4
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...
January 17, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28090684/predict-pd-an-online-approach-to-prospectively-identify-risk-indicators-of-parkinson-s-disease
#5
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...
January 16, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28071824/heart-rate-variability-in-leucine-rich-repeat-kinase-2-associated-parkinson-s-disease
#6
Naomi P Visanji, Grace S Bhudhikanok, Tiago A Mestre, Taneera Ghate, Kaviraj Udupa, Amaal AlDakheel, Barbara S Connolly, Carmen Gasca-Salas, Drew S Kern, Jennifer Jain, Elizabeth J Slow, Achinoam Faust-Socher, Sam Kim, Ruksana Azhu Valappil, Farah Kausar, Ekaterina Rogaeva, J William Langston, Caroline M Tanner, Birgitt Schüle, Anthony E Lang, Samuel M Goldman, Connie Marras
BACKGROUND: Heart rate variability is reduced in idiopathic PD, indicating cardiac autonomic dysfunction likely resulting from peripheral autonomic synucleinopathy. Little is known about heart rate variability in leucine-rich repeat kinase 2-associated PD. OBJECTIVES: This study investigated heart rate variability in LRRK2-associated PD. METHODS: Resting electrocardiograms were obtained from 20 individuals with LRRK2-associated PD, 37 nonmanifesting carriers, 48 related noncarriers, 26 idiopathic PD patients, and 32 controls...
January 10, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28041945/knockdown-transgenic-lrrk-drosophila-resists-paraquat-induced-locomotor-impairment-and-neurodegeneration-a-therapeutic-strategy-for-parkinson-s-disease
#7
Diana Quintero-Espinosa, Marlene Jimenez-Del-Rio, Carlos Velez-Pardo
Leucine-rich repeat kinase 2 (LRRK2) has been linked to familial and sporadic Parkinson's disease. However, it is still unresolved whether LRRK2 in dopaminergic (DAergic) neurons may or may not aggravate the phenotype. We demonstrate that knocking down (KD) the Lrrk gene by RNAi in DAergic neurons untreated or treated with paraquat (PQ) neither affected the number of DAergic clusters, tyrosine hydroxylase (TH) protein levels, lifespan nor locomotor activity when compared to control (i.e. TH/+) flies. KD transgenic Lrrk flies dramatically increased locomotor activity in presence of TH enzyme inhibitor alpha-methyl-para-tyrosine (aMT), whereas no effect on lifespan was observed in both fly lines...
December 29, 2016: Brain Research
https://www.readbyqxmd.com/read/28028237/nrf2-mitigates-lrrk2-and-%C3%AE-synuclein-induced-neurodegeneration-by-modulating-proteostasis
#8
Gaia Skibinski, Vicky Hwang, Dale Michael Ando, Aaron Daub, Alicia K Lee, Abinaya Ravisankar, Sara Modan, Mariel M Finucane, Benjamin A Shaby, Steven Finkbeiner
Mutations in leucine-rich repeat kinase 2 (LRRK2) and α-synuclein lead to Parkinson's disease (PD). Disruption of protein homeostasis is an emerging theme in PD pathogenesis, making mechanisms to reduce the accumulation of misfolded proteins an attractive therapeutic strategy. We determined if activating nuclear factor erythroid 2-related factor (Nrf2), a potential therapeutic target for neurodegeneration, could reduce PD-associated neuron toxicity by modulating the protein homeostasis network. Using a longitudinal imaging platform, we visualized the metabolism and location of mutant LRRK2 and α-synuclein in living neurons at the single-cell level...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28011712/genome-wide-association-study-of-parkinson-s-disease-in-east-asians
#9
Jia Nee Foo, Louis C Tan, Ishak D Irwan, Wing-Lok Au, Hui Qi Low, Kumar-M Prakash, Azlina Ahmad-Annuar, Jinxin Bei, Anne Yy Chan, Chiung Mei Chen, Yi-Chun Chen, Sun Ju Chung, Hao Deng, Shen-Yang Lim, Vincent Mok, Hao Pang, Zhong Pei, Rong Peng, Hui-Fang Shang, Kyuyoung Song, Ai Huey Tan, Yih-Ru Wu, Tin Aung, Ching-Yu Cheng, Fook Tim Chew, Soo-Hong Chew, Siow-Ann Chong, Richard P Ebstein, Jimmy Lee, Seang-Mei Saw, Adeline Seow, Mythily Subramaniam, E-Shyong Tai, Eranga N Vithana, Tien-Yin Wong, Khai Koon Heng, Wee-Yang Meah, Chiea Chuen Khor, Hong Liu, Furen Zhang, Jianjun Liu, Eng-King Tan
Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analyzing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters, adjusted for the first three principal components...
December 22, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27992764/microrna-712-restrains-macrophage-pro-inflammatory-responses-by-targeting-lrrk2-leading-to-restoration-of-insulin-stimulated-glucose-uptake-by-myoblasts
#10
Malathi Talari, Tapan Kumar Singh Nayak, Vasundhara Kain, Phanithi Prakash Babu, Parimal Misra, Kishore V L Parsa
Chronic inflammatory diseases such as insulin resistance, Type 2 diabetes, neurodegenerative diseases etc., are shown to be caused due to imbalanced activation states of macrophages. MicroRNAs which are transcriptional/post-transcriptional regulators of gene expression drive several pathophysiological processes including macrophage polarization. However the functional role of microRNAs in regulating inflammation induced insulin resistance is ill defined. In our current study we observed that the expression of miR-712 was reduced in macrophages exposed to LPS and IFN-γ...
December 16, 2016: Molecular Immunology
https://www.readbyqxmd.com/read/27975167/lrrk2-expression-is-deregulated-in-fibroblasts-and-neurons-from-parkinson-patients-with-mutations-in-pink1
#11
Garikoitz Azkona, Rakel López de Maturana, Patricia Del Rio, Amaya Sousa, Nerea Vazquez, Amaia Zubiarrain, Daniel Jimenez-Blasco, Juan P Bolaños, Blas Morales, Georg Auburger, José Matias Arbelo, Rosario Sánchez-Pernaute
Mutations in PINK1 (PARK6), a serine/threonine kinase involved in mitochondrial homeostasis, are associated with early onset Parkinson's disease. Fibroblasts from Parkinson's disease patients with compound heterozygous mutations in exon 7 (c.1488 + 1G > A; c.1252_1488del) showed no apparent signs of mitochondrial impairment. To elucidate changes primarily caused by lack of functional PINK1, we over-expressed wild-type PINK1, which induced a significant downregulation of LRRK2 (PARK8). Indeed, we found that LRRK2 protein basal levels were significantly higher in the mutant PINK1 fibroblasts...
December 14, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27943640/the-discovery-of-lrrk2-p-r1441s-a-novel-mutation-for-parkinson-s-disease-adds-to-the-complexity-of-a-mutational-hotspot
#12
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
No abstract text is available yet for this article.
January 2017: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
https://www.readbyqxmd.com/read/27943591/effects-of-lrrk2-inhibitors-on-nigrostriatal-dopaminergic-neurotransmission
#13
Qi Qin, Lian-Teng Zhi, Xian-Ting Li, Zhen-Yu Yue, Guo-Zhong Li, Hui Zhang
INTRODUCTION: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent cause of familial and sporadic Parkinson's disease (PD). Because most pathogenic LRRK2 mutations result in enhanced kinase activity, it suggests that LRRK2 inhibitors may serve as a potential treatment for PD. To evaluate whether LRRK2 inhibitors are effective therapies for PD, it is crucial to know whether LRRK2 inhibitors will affect dopaminergic (DAergic) neurotransmission. However, to date, there is no study to investigate the impact of LRRK2 inhibitors on DAergic neurotransmission...
December 9, 2016: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/27939437/the-dual-enzyme-lrrk2-hydrolyzes-gtp-in-both-its-gtpase-and-kinase-domains-in-vitro
#14
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...
December 8, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27936930/different-contributions-of-cdkal1-kif21b-and-lrrk2-muc19-polymorphisms-to-sapho-syndrome-rheumatoid-arthritis-ankylosing-spondylitis-and-seronegative-spondyloarthropathy
#15
Nan Li, Junfen Ma, Kai Li, Changlong Guo, Liang Ming
OBJECTIVES: Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, rheumatoid arthritis (RA), ankylosing spondylitis (AS), and seronegative spondyloarthropathy (SPA) are autoimmune diseases of unknown etiology, which share some clinical manifestations in common. Previous family-based investigations support genetic contributions to the susceptibility of these diseases. The current study evaluated whether three previously reported AS-associated single-nucleotide polymorphisms (SNPs), rs6908425 T>C in CDKAL1, rs11584383 T>C near KIF21B, and rs11175593 C>T near LRRK2/MUC19, have any genetic overlap across multiple autoimmune diseases including SAPHO syndrome, RA, AS, and SPA...
December 12, 2016: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/27927216/lrrk2-at-the-interface-of-autophagosomes-endosomes-and-lysosomes
#16
REVIEW
Dorien A Roosen, Mark R Cookson
Over the past 20 years, substantial progress has been made in identifying the underlying genetics of Parkinson's disease (PD). Of the known genes, LRRK2 is a major genetic contributor to PD. However, the exact function of LRRK2 remains to be elucidated. In this review, we discuss how familial forms of PD have led us to hypothesize that alterations in endomembrane trafficking play a role in the pathobiology of PD. We will discuss the major observations that have been made to elucidate the role of LRRK2 in particular, including LRRK2 animal models and high-throughput proteomics approaches...
December 7, 2016: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/27925204/rabs-membrane-dynamics-and-parkinson-s-disease
#17
REVIEW
Bor Luen Tang
Genes encoding cellular membrane trafficking components, namely RAB7L1 and RAB39B, are more recently recognized factors associated with Parkinson's disease (PD). Encoded by a gene within the PARK16 locus, RAB7L1 interacts with Leucine-rich repeat kinase 2 (LRRK2) to act in intracellular transport processes that are likely important for neuronal survival and function. LRRK2 also directly phosphorylates a number of other Rab proteins. On the other hand, nonsense and missense mutations of the X-chromosome localized RAB39B were shown to underlie X-linked intellectual disability (ID) in male patients with early-onset PD...
December 7, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27914807/phosphorylation-of-p53-by-lrrk2-induces-microglial-tumor-necrosis-factor-%C3%AE-mediated-neurotoxicity
#18
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/27913672/first-model-of-dimeric-lrrk2-the-challenge-of-unrevealing-the-structure-of-a-multidomain-parkinson-s-associated-protein
#19
REVIEW
Giambattista Guaitoli, Bernd K Gilsbach, Francesco Raimondi, Christian Johannes Gloeckner
Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common cause of Mendelian forms of Parkinson's disease, among autosomal dominant cases. Its gene product, LRRK2, is a large multidomain protein that belongs to the Roco protein family exhibiting GTPase and kinase activity, with the latter activity increased by pathogenic mutations. To allow rational drug design against LRRK2 and to understand the cross-regulation of the G- and the kinase domain at a molecular level, it is key to solve the three-dimensional structure of the protein...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913671/l-rrk-de-triomphe-a-solution-for-lrrk2-gtpase-activity
#20
REVIEW
Jonathon Nixon-Abell, Daniel C Berwick, Kirsten Harvey
Leucine-rich repeat kinase 2 (LRRK2) is a central protein in the pathogenesis of Parkinson's disease (PD), yet its normal function has proved stubbornly hard to elucidate. Even though it remains unclear how pathogenic mutations affect LRRK2 to cause PD, recent findings provide increasing cause for optimism. We summarise here the developing consensus over the effect of pathogenic mutations in the Ras of complex proteins and C-terminal of Roc domains on LRRK2 GTPase activity. This body of work has been greatly reinforced by our own study of the protective R1398H variant contained within the LRRK2 GTPase domain...
December 15, 2016: Biochemical Society Transactions
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