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https://www.readbyqxmd.com/read/28639421/penetrance-estimate-of-lrrk2-p-g2019s-mutation-in-individuals-of-non-ashkenazi-jewish-ancestry
#1
Annie J Lee, Yuanjia Wang, Roy N Alcalay, Helen Mejia-Santana, Rachel Saunders-Pullman, Susan Bressman, Jean-Christophe Corvol, Alexis Brice, Suzanne Lesage, Graziella Mangone, Eduardo Tolosa, Claustre Pont-Sunyer, Dolores Vilas, Birgitt Schüle, Farah Kausar, Tatiana Foroud, Daniela Berg, Kathrin Brockmann, Stefano Goldwurm, Chiara Siri, Rosanna Asselta, Javier Ruiz-Martinez, Elisabet Mondragón, Connie Marras, Taneera Ghate, Nir Giladi, Anat Mirelman, Karen Marder
BACKGROUND: Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80...
June 22, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28598236/destructive-cellular-paths-underlying-familial-and-sporadic-parkinson-disease-converge-on-mitophagy
#2
Xinnan Wang
The knowledge gap separating the molecular and cellular underpinnings of Parkinson disease (PD) and its pathology hinders treatment innovation. Adding to this difficulty is the lack of a reliable biomarker for PD. Our previous studies identify a link of 2 PD proteins, PINK1 and PRKN/Parkin to a mitochondrial motor/adaptor RHOT1/Miro-1, which mediates mitochondrial motility and mitophagy. Here we review our recent paper showing that a third PD protein, LRRK2, also targets RHOT1 and regulates mitophagy, and pathogenic LRRK2 disrupts this function...
June 9, 2017: Autophagy
https://www.readbyqxmd.com/read/28588547/improving-dual-task-walking-paradigms-to-detect-prodromal-parkinson-s-and-alzheimer-s-diseases
#3
Maroua Belghali, Nathalie Chastan, Damien Davenne, Leslie M Decker
Gait control is a complex movement, relying on spinal, subcortical, and cortical structures. The presence of deficits in one or more of these structures will result in changes in gait automaticity and control, as is the case in several neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). By reviewing recent findings in this field of research, current studies have shown that gait performance assessment under dual-task conditions could contribute to predict both of these diseases...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28586827/genome-wide-pleiotropy-between-parkinson-disease-and-autoimmune-diseases
#4
Aree Witoelar, Iris E Jansen, Yunpeng Wang, Rahul S Desikan, J Raphael Gibbs, Cornelis Blauwendraat, Wesley K Thompson, Dena G Hernandez, Srdjan Djurovic, Andrew J Schork, Francesco Bettella, David Ellinghaus, Andre Franke, Benedicte A Lie, Linda K McEvoy, Tom H Karlsen, Suzanne Lesage, Huw R Morris, Alexis Brice, Nicholas W Wood, Peter Heutink, John Hardy, Andrew B Singleton, Anders M Dale, Thomas Gasser, Ole A Andreassen, Manu Sharma
Importance: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. Objectives: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach...
June 5, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/28584093/treatment-with-diphenyl-pyrazole-compound-anle138b-c-reveals-that-%C3%AE-synuclein-protects-melanoma-cells-from-autophagic-cell-death
#5
Elisa Turriani, Diana F Lázaro, Sergey Ryazanov, Andrei Leonov, Armin Giese, Margarete Schön, Michael P Schön, Christian Griesinger, Tiago F Outeiro, Donna J Arndt-Jovin, Dorothea Becker
Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson's disease. Because no evidence could be obtained that genetic factors are the reason for the association between these two diseases, we hypothesized that of the three major Parkinson's disease-related proteins-α-synuclein, LRRK2, and Parkin-α-synuclein might be a major link. Our data, presented here, demonstrate that α-synuclein promotes the survival of primary and metastatic melanoma cells, which is the exact opposite of the effect that α-synuclein has on dopaminergic neurons, where its accumulation causes neuronal dysfunction and death...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28582422/role-of-lrrk2-in-the-regulation-of-dopamine-receptor-trafficking
#6
Mauro Rassu, Maria Grazia Del Giudice, Simona Sanna, Jean Marc Taymans, Michele Morari, Alberto Brugnoli, Martina Frassineti, Alessandra Masala, Sonia Esposito, Manuela Galioto, Cristiana Valle, Maria Teresa Carri, Alice Biosa, Elisa Greggio, Claudia Crosio, Ciro Iaccarino
Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson's disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking that in turn may regulate different aspects of neuronal physiology. We have analyzed the role of LRRK2 in regulating dopamine receptor D1 (DRD1) and D2 (DRD2) trafficking. DRD1 and DRD2 are the most abundant dopamine receptors in the brain...
2017: PloS One
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
#7
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...
May 31, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28568905/tmem230-how-does-it-fit-in-the-etiology-and-pathogenesis-of-parkinson-s-disease
#8
REVIEW
Wim Mandemakers, Marialuisa Quadri, Maria Stamelou, Vincenzo Bonifati
Mutations in the transmembrane protein 230 (TMEM230) gene were recently identified in a large Canadian pedigree and 7 smaller Chinese families, nominating TMEM230 as the third gene causing a Mendelian form of late onset Parkinson's disease (PD) with typical Lewy-body pathology (after synuclein alpha (SNCA) and leucine rich repeat kinase 2 (LRRK2)). The protein encoded by TMEM230 remains largely uncharacterized, but initial evidence points to roles in the trafficking of recycling vesicles, retromers, and endosomes, suggesting intriguing links to the pathways targeted by other PD-causing genes...
June 1, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28553204/leucine-rich-repeat-kinase-2-lrrk2-stimulates-il-1%C3%AE-mediated-inflammatory-signaling-through-phosphorylation-of-rcan1
#9
Kyung A Han, Lang Yoo, Jee Y Sung, Sun A Chung, Ji W Um, Hyeyoung Kim, Wongi Seol, Kwang C Chung
Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase having mixed lineage kinase-like and GTPase domains, controlling neurite outgrowth and neuronal cell death. Evidence suggests that LRRK2 is involved in innate immune response signaling, but the underlying mechanism is yet unknown. A novel protein inhibitor of phosphatase 3B, RCAN1, is known to positively regulate inflammatory signaling through modulation of several intracellular targets of interleukins in immune cells. In the present study, we report that LRRK2 phosphorylates RCAN1 (RCAN1-1S) and is markedly up-regulated during interleukin-1β (IL-1β) treatment...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28541025/structural-genomic-variations-and-parkinson-s-disease
#10
Sara Bandrés-Ciga, Clara Ruz, Francisco J Barrero, Francisco Escamilla-Sevilla, Javier Pelegrina, Francisco Vives, Raquel Duran
Parkinson's disease (PD) is the second most common neurodegenerative disease, whose prevalence is projected to be between 8.7 and 9.3 million by 2030. Until about 20 years ago, PD was considered to be the textbook example of a "nongenetic" disorder. Nowadays, PD is generally considered a multifactorial disorder that arises from the combination and complex interaction of genes and environmental factors. To date, a total of 7 genes including SNCA, LRRK2, PARK2, DJ-1, PINK 1, VPS35 and ATP13A2 have been seen to cause unequivocally Mendelian PD...
May 25, 2017: Minerva Medica
https://www.readbyqxmd.com/read/28529829/connecting-ca-2-and-lysosomes-to-parkinson-disease
#11
Bethan S Kilpatrick
The neurodegenerative movement disorder Parkinson disease (PD) is prevalent in the aged population. However, the underlying mechanisms that trigger disease are unclear. Increasing work implicates both impaired Ca(2+) signalling and lysosomal dysfunction in neuronal demise. Here I aim to connect these distinct processes by exploring the evidence that lysosomal Ca(2+) signalling is disrupted in PD. In particular, I highlight defects in lysosomal Ca(2+) content and signalling through NAADP-regulated two-pore channels in patient fibroblasts harbouring mutations in the PD-linked genes, GBA1 and LRRK2...
June 1, 2016: Messenger
https://www.readbyqxmd.com/read/28511254/genetic-forms-of-parkinson-s-disease
#12
Christine Y Kim, Roy N Alcalay
One of the greatest advances in Parkinson's disease (PD) research in the past two decades has been a better understanding of PD genetics. Of the many candidate genes investigated, the best studied include LRRK2, SNCA, VPS35, Parkin, PINK1, and DJ1. The authors review the key clinical features of these monogenic forms, as well as for the prevalent risk factor gene, GBA, including the phenotype, clinical course, and treatment response. They also outline areas for future investigation: longitudinal studies of PD's clinical course, the identification of its premotor manifestations, and its specific mechanisms of pathogenicity...
April 2017: Seminars in Neurology
https://www.readbyqxmd.com/read/28508149/parkinson-s-disease-associated-mutant-lrrk2-mediated-inhibition-of-mirna-activity-is-antagonized-by-trim32
#13
Laura Gonzalez-Cano, Ingeborg Menzl, Johan Tisserand, Sarah Nicklas, Jens C Schwamborn
Parkinson's disease (PD) is the second most common neurodegenerative disorder. Accumulating evidences suggest that PD might have a strong neurodevelopmental component. Among the genetic cases, mutations in the leucine-rich repeat kinase 2 (LRRK2) are well known to be disease causing. Although the molecular mechanism of the pathogenic LRRK2 function is not fully clear, inhibition of microRNA (miRNA) activity has been suggested to be among the pathogenic LRRK2 targets. Here, we demonstrate that the miRNA activity inhibition function of pathogenic LRRK2 is directly antagonized by the neuronal cell fate determinant TRIM32...
May 15, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28502042/tale-of-the-good-and-the-bad-cdk5-remodeling-of-the-actin-cytoskeleton-in-the-brain
#14
REVIEW
Kavita Shah, Sandra Rossie
Cdk5 kinase, a cyclin-dependent kinase family member, is a key regulator of cytoskeletal remodeling in the brain. Cdk5 is essential for brain development during embryogenesis. After birth, it is essential for numerous neuronal processes such as learning and memory formation, drug addiction, pain signaling, and long-term behavior changes, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity is deregulated in various brain disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemic stroke, resulting in profound remodeling of the neuronal cytoskeleton, loss of synapses, and ultimately neurodegeneration...
May 13, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28487191/human-lrrk2-g2019s-mutation-represses-post-synaptic-protein-psd95-and-causes-cognitive-impairment-in-transgenic-mice
#15
Samuel O Adeosun, Xu Hou, Baoying Zheng, Heather L Melrose, Thomas Mosley, Jun Ming Wang
BACKGROUND: LRRK2 G2019S mutation is associated with increased kinase activity and is the most common mutation associated with late-onset PD. However, the transgenic mouse model has not recapitulated cardinal PD-related motor phenotypes. Non-motor symptoms of PD including cognitive impairments are very common and may appear earlier than the motor symptoms. The objective of this study was to determine whether human LRRK2 with G2019S mutation causes hippocampus-dependent cognitive deficits in mice...
July 2017: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/28482024/vps35-in-cooperation-with-lrrk2-regulates-synaptic-vesicle-endocytosis-through-the-endosomal-pathway-in-drosophila
#16
Tsuyoshi Inoshita, Taku Arano, Yuka Hosaka, Hongrui Meng, Yujiro Umezaki, Sakiko Kosugi, Takako Morimoto, Masato Koike, Hui-Yun Chang, Yuzuru Imai, Nobutaka Hattori
Mutations of the retromer component Vps35 and endosomal kinase LRRK2 are linked to autosomal dominant forms of familial Parkinson's disease (PD). However, the physiological and pathological roles of Vps35 and LRRK2 in neuronal functions are poorly understood. Here, we demonstrated that the loss of Drosophila Vps35 (dVps35) affects synaptic vesicle recycling, dopaminergic synaptic release and sleep behavior associated with dopaminergic activity, which is rescued by the expression of wild-type dVps35 but not the PD-associated mutant dVps35 D647N...
May 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28472425/prodromal-parkinsonism-and-neurodegenerative-risk-stratification-in-rem-sleep-behaviour-disorder
#17
Thomas R Barber, Michael Lawton, Michal Rolinski, Samuel Evetts, Fahd Baig, Claudio Ruffmann, Aimie Gornall, Johannes C Klein, Christine Lo, Gary Dennis, Oliver Bandmann, Timothy Quinnell, Zenobia Zaiwalla, Yoav Ben-Shlomo, Michele Tm Hu
Objectives.: REM sleep behaviour disorder (RBD) is the most specific marker of prodromal alpha-synucleinopathies. We sought to delineate the baseline clinical characteristics of RBD and evaluate risk stratification models. Methods.: Clinical assessments were performed in 171 RBD, 296 control and 119 untreated Parkinson's (PD) subjects. Putative risk measures were assessed as predictors of prodromal neurodegeneration and Movement Disorders Society (MDS) criteria for prodromal PD were applied...
May 4, 2017: Sleep
https://www.readbyqxmd.com/read/28465860/lrrk2-g2019s-mutation-prevalence-and-clinical-features-in-moroccans-with-parkinson-s-disease
#18
Ahmed Bouhouche, Houyam Tibar, Rafiqua Ben El Haj, Khalil El Bayad, Rachid Razine, Sanaa Tazrout, Asmae Skalli, Naima Bouslam, Loubna Elouardi, Ali Benomar, Mohammed Yahyaoui, Wafa Regragui
Background. The LRRK2 G2019S mutation is the most common genetic determinant of Parkinson's disease (PD) identified to date. This mutation, reported in both familial and sporadic PD, occurs at elevated frequencies in Maghreb population. In the present study, we examined the prevalence of the G2019S mutation in the Moroccan population and we compared the motor and nonmotor phenotype of G2019S carriers to patients with idiopathic Parkinson's disease. Methods. 100 PD patients were assessed for motor and nonmotor symptoms, current medication, and motor complication including motor fluctuations and dyskinesia...
2017: Parkinson's Disease
https://www.readbyqxmd.com/read/28462461/erratum-to-synthesis-and-in-vitro-and-in-vivo-evaluation-of-3-h-lrrk2-in-1-as-a-novel-radioligand-for-lrrk2
#19
Noeen Malik, Andrew N Gifford, Johan Sandell, Daniel Tuchman, Yu-Shin Ding
No abstract text is available yet for this article.
May 1, 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
https://www.readbyqxmd.com/read/28458632/the-monoamine-brainstem-reticular-formation-as-a-paradigm-for-re-defining-various-phenotypes-of-parkinson-s-disease-owing-genetic-and-anatomical-specificity
#20
REVIEW
Stefano Gambardella, Rosangela Ferese, Francesca Biagioni, Carla L Busceti, Rosa Campopiano, Anna M P Griguoli, Fiona Limanaqi, Giuseppe Novelli, Marianna Storto, Francesco Fornai
The functional anatomy of the reticular formation (RF) encompasses a constellation of brain regions which are reciprocally connected to sub-serve a variety of functions. Recent evidence indicates that neuronal degeneration within one of these regions spreads synaptically along brainstem circuitries. This is exemplified by the recruitment of various brainstem reticular nuclei in specific Parkinson's disease (PD) phenotypes, and by retrospective analysis of lethargic post-encephalitic parkinsonism. In fact, the spreading to various monoamine reticular nuclei can be associated with occurrence of specific motor and non-motor symptoms (NMS)...
2017: Frontiers in Cellular Neuroscience
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