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https://www.readbyqxmd.com/read/29917075/proteomic-analysis-reveals-co-ordinated-alterations-in-protein-synthesis-and-degradation-pathways-in-lrrk2-knockout-mice
#1
Laura Pellegrini, David N Hauser, Yan Li, Adamantios Mamais, Alexandra Beilina, Ravindran Kumaran, Andrea Wetzel, George Heaton, Iakov Rudenko, Mor Alkaslasi, Natalie Ivanina, Heather L Melrose, Mark R Cookson, Kirsten Harvey
Mutations in leucine-rich repeat kinase 2 (LRRK2) segregate with familial Parkinson's disease (PD) and genetic variation around LRRK2 contributes to risk of sporadic disease. Although knockout of LRRK2 or knock-in of pathogenic mutations into the mouse germline does not result in a PD phenotype, several defects have been reported in the kidneys of LRRK2 knockout mice. To understand LRRK2 function in vivo, we used an unbiased approach to determine which protein pathways are affected in LRRK2 knockout kidneys...
June 18, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29908325/dopamine-d2-receptor-activation-potently-inhibits-striatal-glutamatergic-transmission-in-a-g2019s-lrrk2-genetic-model-of-parkinson-s-disease
#2
Alessandro Tozzi, Valentina Durante, Guendalina Bastioli, Petra Mazzocchetti, Salvatore Novello, Alessandro Mechelli, Michele Morari, Cinzia Costa, Andrea Mancini, Massimiliano Di Filippo, Paolo Calabresi
Among genetic abnormalities identified in Parkinson's disease (PD), mutations of the leucine-rich repeat kinase2 (LRRK2) gene, such as the G2019S missense mutation linked to enhanced kinase activity, are the most common. While the complex role of LRRK2 has not been fully elucidated, evidence that mutated kinase activity affects synaptic transmission has been reported. Thus, our aim was to explore possible early alterations of neurotransmission produced by the G2019S LRRK2 mutation in PD. We performed electrophysiological patch-clamp recordings of striatal spiny projection neurons (SPNs) in the G2019S-Lrrk2 knock-in (KI) mouse model of PD, in D1994S kinase-dead (KD), Lrrk2 knock-out (KO) and wild-type (WT) mice...
June 13, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29907646/genetic-modifiers-of-neurodegeneration-in-a-drosophila-model-of-parkinson-s-disease
#3
Sierra Lavoy, Vinita G Chittoor-Vinod, Clement Y Chow, Ian Martin
Disease phenotypes can be highly variable among individuals with the same pathogenic mutation. There is increasing evidence that background genetic variation is a strong driver of disease variability in addition to the influence of environment. To understand the genotype-phenotype relationship that determines the expressivity of a pathogenic mutation, a large number of backgrounds must be studied. This can be efficiently achieved using model organism collections such as the Drosophila Genetic Reference Panel (DGRP)...
June 15, 2018: Genetics
https://www.readbyqxmd.com/read/29884186/exhaustion-of-mitochondrial-and-autophagic-reserve-may-contribute-to-the-development-of-lrrk2-g2019s-parkinson-s-disease
#4
Diana Luz Juárez-Flores, Ingrid González-Casacuberta, Mario Ezquerra, María Bañó, Francesc Carmona-Pontaque, Marc Catalán-García, Mariona Guitart-Mampel, Juan José Rivero, Ester Tobias, Jose Cesar Milisenda, Eduard Tolosa, Maria Jose Marti, Ruben Fernández-Santiago, Francesc Cardellach, Constanza Morén, Glòria Garrabou
BACKGROUND: Mutations in leucine rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). Mitochondrial and autophagic dysfunction has been described as etiologic factors in different experimental models of PD. We aimed to study the role of mitochondria and autophagy in LRRK2 G2019S -mutation, and its relationship with the presence of PD-symptoms. METHODS: Fibroblasts from six non-manifesting LRRK2 G2019S -carriers (NM-LRRK2 G2019S ) and seven patients with LRRK2 G2019S -associated PD (PD-LRRK2 G2019S ) were compared to eight healthy controls (C)...
June 8, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29846835/cerebral-imaging-markers-of-gba-and-lrrk2-related-parkinson-s-disease-and-their-first-degree-unaffected-relatives
#5
Avner Thaler, Efrat Kliper, Inbal Maidan, Talia Herman, Keren Rosenberg-Katz, Noa Bregman, Tanya Gurevich, Tamara Shiner, Jeffrey M Hausdorff, Avi Orr-Urtreger, Nir Giladi, Anat Mirelman
Cerebral atrophy has been detected in patients with Parkinson's disease (PD) both with and without dementia, however differentiation based on genetic status has thus far not yielded robust findings. We assessed cortical thickness and subcortical volumes in a cohort of PD patients and healthy controls carriers of the G2019S mutation in the LRRK2 gene and the common GBA mutations, in an attempt to determine whether genetic status influences structural indexes. Cortical thickness and subcortical volumes were computed and compared between six groups of participants; idiopathic PD, GBA-PD, LRRK2-PD, non-manifesting non-carriers (NMNC), GBA-non-manifesting carriers (NMC) and LRRK2-NMC utilizing the FreeSurfer software program...
May 30, 2018: Brain Topography
https://www.readbyqxmd.com/read/29760073/regulation-of-myeloid-cell-phagocytosis-by-lrrk2-via-wave2-complex-stabilization-is-altered-in-parkinson-s-disease
#6
Kwang Soo Kim, Paul C Marcogliese, Jungwoo Yang, Steve M Callaghan, Virginia Resende, Elizabeth Abdel-Messih, Connie Marras, Naomi P Visanji, Jana Huang, Michael G Schlossmacher, Laura Trinkle-Mulcahy, Ruth S Slack, Anthony E Lang, David S Park
Leucine-rich repeat kinase 2 ( LRRK2 ) has been implicated in both familial and sporadic Parkinson's disease (PD), yet its pathogenic role remains unclear. A previous screen in Drosophila identified Scar/WAVE (Wiskott-Aldrich syndrome protein-family verproline) proteins as potential genetic interactors of LRRK2 Here, we provide evidence that LRRK2 modulates the phagocytic response of myeloid cells via specific modulation of the actin-cytoskeletal regulator, WAVE2. We demonstrate that macrophages and microglia from LRRK2-G2019S PD patients and mice display a WAVE2-mediated increase in phagocytic response, respectively...
May 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29719501/acetylome-in-human-fibroblasts-from-parkinson-s-disease-patients
#7
Sokhna M S Yakhine-Diop, Mario Rodríguez-Arribas, Guadalupe Martínez-Chacón, Elisabet Uribe-Carretero, Rubén Gómez-Sánchez, Ana Aiastui, Adolfo López de Munain, José M Bravo-San Pedro, Mireia Niso-Santano, Rosa A González-Polo, José M Fuentes
Parkinson's disease (PD) is a multifactorial neurodegenerative disorder. The pathogenesis of this disease is associated with gene and environmental factors. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of familial and sporadic PD. Moreover, posttranslational modifications, including protein acetylation, are involved in the molecular mechanism of PD. Acetylation of lysine proteins is a dynamic process that is modulated in PD. In this descriptive study, we characterized the acetylated proteins and peptides in primary fibroblasts from idiopathic PD (IPD) and genetic PD harboring G2019S or R1441G LRRK2 mutations...
2018: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29665080/clustering-of-motor-and-nonmotor-traits-in-leucine-rich-repeat-kinase-2-g2019s-parkinson-s-disease-nonparkinsonian-relatives-a-multicenter-family-study
#8
Tiago A Mestre, Claustre Pont-Sunyer, Farah Kausar, Naomi P Visanji, Taneera Ghate, Barbara S Connolly, Carmen Gasca-Salas, Drew S Kern, Jennifer Jain, Elizabeth J Slow, Achinoam Faust-Socher, Meike Kasten, Pettarusp M Wadia, Cindy Zadikoff, Prakash Kumar, Ronald M de Bie, Teri Thomsen, Anthony E Lang, Birgitt Schüle, Christine Klein, Eduardo Tolosa, Connie Marras
OBJECTIVES: The objective of this study was to determine phenotypic features that differentiate nonparkinsonian first-degree relatives of PD leucine-rich repeat kinase 2 (LRRK2) G2019S multiplex families, regardless of carrier status, from healthy controls because nonparkinsonian individuals in multiplex families seem to share a propensity to present neurological features. METHODS: We included nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases and unrelated healthy controls participating in established multiplex family LRRK2 cohorts...
April 17, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29627023/motor-and-non-motor-features-of-parkinson-s-disease-in-lrrk2-g2019s-carriers-versus-matched-controls
#9
Steven A Gunzler, David E Riley, Shu G Chen, Curtis M Tatsuoka, William M Johnson, John J Mieyal, Ellen M Walter, Christina M Whitney, I Jung Feng, Harry Owusu-Dapaah, Shivam O Mittal, Amy L Wilson-Delfosse
INTRODUCTION: LRRK2 G2019S mutation carriers with Parkinson's disease (PD) have been generally indistinguishable from those with idiopathic PD, with the exception of variable differences in some motor and non-motor domains, including cognition, gait, and balance. LRRK2 G2019S is amongst the most common genetic etiologies for PD, particularly in Ashkenazi Jewish (AJ) populations. METHODS: This cross-sectional data collection study sought to clarify the phenotype of LRRK2 G2019S mutation carriers with PD...
May 15, 2018: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/29603409/application-of-the-movement-disorder-society-prodromal-criteria-in-healthy-g2019s-lrrk2-carriers
#10
Anat Mirelman, Rachel Saunders-Pullman, Roy N Alcalay, Shiran Shustak, Avner Thaler, Tanya Gurevich, Deborah Raymond, Helen Mejia-Santana, Martha Orbe Reilly, Laurie Ozelius, Lorraine Clark, Mali Gana-Weisz, Anat Bar-Shira, Avi Orr-Utreger, Susan B Bressman, Karen Marder, Nir Giladi
BACKGROUND: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD. OBJECTIVES: We aimed to evaluate, for the first time, the criteria in first-degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters. METHODS: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49...
March 30, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29550548/age-related-pathology-after-adenoviral-overexpression-of-the-leucine-rich-repeat-kinase-2-in-the-mouse-striatum
#11
Astrid Kritzinger, Boris Ferger, Frank Gillardon, Birgit Stierstorfer, Gerald Birk, Stefan Kochanek, Thomas Ciossek
Mutations in leucine-rich repeat kinase 2 (LRRK2) age-dependently cause Parkinson's disease and are associated with several inflammatory diseases. So far, the potential role of LRRK2 expression in glial cells as mediators of neuroinflammation and the influence of aging have not been investigated in viral vector-based LRRK2 animal models. In this study, we compared the effect of striatal injection of high-capacity adenoviral vectors expressing either a kinase-overactive LRRK2 with the familial G2019S mutation or a kinase-inactive LRRK2 variant in young and old C57BL/6J mice...
June 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29519959/p62-sqstm1-is-a-novel-leucine-rich-repeat-kinase-2-lrrk2-substrate-that-enhances-neuronal-toxicity
#12
Alexia F Kalogeropulou, Jing Zhao, Marc F Bolliger, Anna Memou, Shreya Narasimha, Tyler P Molitor, William H Wilson, Hardy J Rideout, R Jeremy Nichols
Autosomal-dominant, missense mutations in the leucine-rich repeat protein kinase 2 ( LRRK2 ) gene are the most common genetic predisposition to develop Parkinson's disease (PD). LRRK2 kinase activity is increased in several pathogenic mutations (N1437H, R1441C/G/H, Y1699C, G2019S), implicating hyperphosphorylation of a substrate in the pathogenesis of the disease. Identification of the downstream targets of LRRK2 is a crucial endeavor in the field to understand LRRK2 pathway dysfunction in the disease. We have identified the signaling adapter protein p62/SQSTM1 as a novel endogenous interacting partner and a substrate of LRRK2...
April 9, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29473656/%C3%AE-synuclein-snca-but-not-dynamin-3-dnm3-influences-age-at-onset-of-leucine-rich-repeat-kinase-2-lrrk2-parkinson-s-disease-in-spain
#13
Rubén Fernández-Santiago, Alicia Garrido, Jon Infante, Isabel González-Aramburu, María Sierra, Manel Fernández, Francesc Valldeoriola, Esteban Muñoz, Yaroslau Compta, María-José Martí, José Ríos, Eduardo Tolosa, Mario Ezquerra
OBJECTIVES: A recent study showed that Arab-Berbers GG homozygous at rs2421947(C/G) in the dynamin 3 gene (DNM3) had 12.5 years earlier age at onset of leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD) (L2PD). We explored whether this variant modulates the L2PD age at onset in Spain. METHODS: We genotyped rs2421947 in 329 participants (210 L2PD patients, 119 L2PD nonmanifesting p.G2019S carriers), and marker rs356219 (A/G) in the α-synuclein gene (SNCA)...
April 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29439717/dysregulated-phosphorylation-of-rab-gtpases-by-lrrk2-induces-neurodegeneration
#14
Ga Ram Jeong, Eun-Hae Jang, Jae Ryul Bae, Soyoung Jun, Ho Chul Kang, Chi-Hu Park, Joo-Ho Shin, Yukio Yamamoto, Keiko Tanaka-Yamamoto, Valina L Dawson, Ted M Dawson, Eun-Mi Hur, Byoung Dae Lee
BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). Elevated kinase activity is associated with LRRK2 toxicity, but the substrates that mediate neurodegeneration remain poorly defined. Given the increasing evidence suggesting a role of LRRK2 in membrane and vesicle trafficking, here we systemically screened Rab GTPases, core regulators of vesicular dynamics, as potential substrates of LRRK2 and investigated the functional consequence of such phosphorylation in cells and in vivo...
February 13, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29434188/dopamine-d2-receptor-mediated-neuroprotection-in-a-g2019s-lrrk2-genetic-model-of-parkinson-s-disease
#15
Alessandro Tozzi, Michela Tantucci, Saverio Marchi, Petra Mazzocchetti, Michele Morari, Paolo Pinton, Andrea Mancini, Paolo Calabresi
Parkinson's disease (PD) is a neurodegenerative disorder in which genetic and environmental factors synergistically lead to loss of midbrain dopamine (DA) neurons. Mutation of leucine-rich repeated kinase2 (Lrrk2) genes is responsible for the majority of inherited familial cases of PD and can also be found in sporadic cases. The pathophysiological role of this kinase has to be fully understood yet. Hyperactivation of Lrrk2 kinase domain might represent a predisposing factor for both enhanced striatal glutamatergic release and mitochondrial vulnerability to environmental factors that are observed in PD...
February 12, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29414418/generation-of-an-induced-pluripotent-stem-cell-line-csc-41-from-a-parkinson-s-disease-patient-carrying-a-p-g2019s-mutation-in-the-lrrk2-gene
#16
Ana Marote, Yuriy Pomeshchik, Anna Collin, Stefano Goldwurm, Nuno J Lamas, Luísa Pinto, António J Salgado, Laurent Roybon
The leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation is the most common genetic cause of Parkinson's disease (PD). An induced pluripotent stem cell (iPSC) line CSC-41 was generated from a 75-year old patient diagnosed with PD caused by a p.G2019S mutation in LRRK2. Skin fibroblasts were reprogrammed using a non-integrating Sendai virus-based technology to deliver OCT3/4, SOX2, c-MYC and KLF4 transcription factors. The generated iPSC line exhibits expression of common pluripotency markers, differentiates into the three germ layers and has a normal karyotype...
April 2018: Stem Cell Research
https://www.readbyqxmd.com/read/29402177/in-vitro-modeling-of-leucine-rich-repeat-kinase-2-lrrk2-g2019s-mediated-parkinson-s-disease-pathology
#17
Scott C Vermilyea, Marina Emborg
Leucine-rich repeat kinase 2 (LRRK2) G2019S (glycine to serine) is the most common mutation associated with sporadic and familial Parkinson's disease (PD) with 80% penetrance by age 70. This mutation is found worldwide, with up to 40% of individuals in the North African Arab population carrying the mutation. Induced pluripotent stem cells (iPSCs) derived from fibroblasts of patients carrying the LRRK2 G2019S mutation have been a critical source of cells for generating dopaminergic neurons and studying G2019S-related pathology...
February 5, 2018: Stem Cells and Development
https://www.readbyqxmd.com/read/29387348/age-induced-neuronal-cell-death-is-enhanced-in-g2019s-lrrk2-mutation-with-increased-rage-expression
#18
Hyun Jin Cho, Chengsong Xie, Huaibin Cai
Background: Leucine-rich repeat kinase 2 (LRRK2) mutations represent the most common genetic cause of sporadic and familial Parkinson's disease (PD). Especially, LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD. Advanced glycation end products (AGEs) are produced in high amounts in diabetes and diverse aging-related disorders, such as cardiovascular disease, renal disease, and neurological disease. AGEs trigger intracellular signaling pathway associated with oxidative stress and inflammation as well as cell death...
2018: Translational Neurodegeneration
https://www.readbyqxmd.com/read/29386392/robust-kinase-and-age-dependent-dopaminergic-and-norepinephrine-neurodegeneration-in-lrrk2-g2019s-transgenic-mice
#19
Yulan Xiong, Stewart Neifert, Senthilkumar S Karuppagounder, Qinfang Liu, Jeannette N Stankowski, Byoung Dae Lee, Han Seok Ko, Yunjong Lee, Jonathan C Grima, Xiaobo Mao, Haisong Jiang, Sung-Ung Kang, Deborah A Swing, Lorraine Iacovitti, Lino Tessarollo, Ted M Dawson, Valina L Dawson
Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson's disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase-dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29369793/alpha-galactosidase-a-activity-in-parkinson-s-disease
#20
R N Alcalay, P Wolf, O A Levy, U J Kang, C Waters, S Fahn, B Ford, S H Kuo, N Vanegas, H Shah, C Liong, S Narayan, M W Pauciulo, W C Nichols, Z Gan-Or, G A Rouleau, W K Chung, P Oliva, J Keutzer, K Marder, X K Zhang
Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University...
April 2018: Neurobiology of Disease
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