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https://www.readbyqxmd.com/read/29760073/regulation-of-myeloid-cell-phagocytosis-by-lrrk2-via-wave2-complex-stabilization-is-altered-in-parkinson-s-disease
#1
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 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29758273/in-silico-experiment-system-for-testing-hypothesis-on-gene-functions-using-three-condition-specific-biological-networks
#2
Chai-Jin Lee, Dongwon Kang, Sangseon Lee, Sunwon Lee, Jaewoo Kang, Sun Kim
Determining functions of a gene requires time consuming, expensive biological experiments. Scientists can speed up this experimental process if the literature information and biological networks can be adequately provided. In this paper, we present a web-based information system that can perform in silico experiments of computationally testing hypothesis on the function of a gene. A hypothesis that is specified in English by the user is converted to genes using a literature and knowledge mining system called BEST...
May 11, 2018: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/29755459/type-i-interferons-autophagy-and-host-metabolism-in-leprosy
#3
REVIEW
Thiago Gomes Toledo Pinto, Leonardo Ribeiro Batista-Silva, Rychelle Clayde Affonso Medeiros, Flávio Alves Lara, Milton Ozório Moraes
For those with leprosy, the extent of host infection by Mycobacterium leprae and the progression of the disease depend on the ability of mycobacteria to shape a safe environment for its replication during early interaction with host cells. Thus, variations in key genes such as those in pattern recognition receptors ( NOD2 and TLR1 ), autophagic flux ( PARK2, LRRK2 , and RIPK2 ), effector immune cytokines ( TNF and IL12 ), and environmental factors, such as nutrition, have been described as critical determinants for infection and disease progression...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29743203/the-parkinson-s-disease-vps35-d620n-mutation-enhances-lrrk2-mediated-rab-protein-phosphorylation-in-mouse-and-human
#4
Rafeeq Mir, Francesca Tonelli, Pawel Lis, Thomas Macartney, Nicole K Polinski, Terina N Martinez, Meng-Yun Chou, Andrew J M Howden, Theresa König, Christoph Hotzy, Ivan Milenkovic, Thomas Brücke, Alexander Zimprich, Esther Sammler, Dario R Alessi
Missense mutations in the LRRK2 and VPS35 genes result in autosomal dominant Parkinson's disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. It is not known how the only thus far described pathogenic VPS35 mutation, [D620N] exerts its effects. We reveal that the VPS35[D620N] knock-in mutation, strikingly elevates LRRK2 mediated phosphorylation of Rab8A, Rab10 and Rab12 in mouse embryonic fibroblasts...
May 9, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29735704/lrrk2-phosphorylation-of-auxilin-mediates-synaptic-defects-in-dopaminergic-neurons-from-patients-with-parkinson-s-disease
#5
Maria Nguyen, Dimitri Krainc
Recently identified Parkinson's disease (PD) genes involved in synaptic vesicle endocytosis, such as DNAJC6 (auxilin), have further implicated synaptic dysfunction in PD pathogenesis. However, how synaptic dysfunction contributes to the vulnerability of human dopaminergic neurons has not been previously explored. Here, we demonstrate that commonly mutated, PD-linked leucine-rich repeat kinase 2 (LRRK2) mediates the phosphorylation of auxilin in its clathrin-binding domain at Ser627. Kinase activity-dependent LRRK2 phosphorylation of auxilin led to differential clathrin binding, resulting in disrupted synaptic vesicle endocytosis and decreased synaptic vesicle density in LRRK2 patient-derived dopaminergic neurons...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29719505/cellular-and-molecular-basis-of-neurodegeneration-in-parkinson-disease
#6
REVIEW
Xian-Si Zeng, Wen-Shuo Geng, Jin-Jing Jia, Lei Chen, Peng-Peng Zhang
It has been 200 years since Parkinson disease (PD) was described by Dr. Parkinson in 1817. The disease is the second most common neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the pathogenesis of PD is still unknown, the research findings from scientists are conducive to understand the pathological mechanisms. It is well accepted that both genetic and environmental factors contribute to the onset of PD. In this review, we summarize the mutations of main seven genes (α-synuclein, LRRK2, PINK1, Parkin, DJ-1, VPS35 and GBA1) linked to PD, discuss the potential mechanisms for the loss of dopaminergic neurons (dopamine metabolism, mitochondrial dysfunction, endoplasmic reticulum stress, impaired autophagy, and deregulation of immunity) in PD, and expect the development direction for treatment of PD...
2018: Frontiers in Aging Neuroscience
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/29707617/detection-of-endogenous-s1292-lrrk2-autophosphorylation-in-mouse-tissue-as-a-readout-for-kinase-activity
#8
Jillian H Kluss, Melissa M Conti, Alice Kaganovich, Aleksandra Beilina, Heather L Melrose, Mark R Cookson, Adamantios Mamais
Parkinson's disease-linked mutations in LRRK2 enhance the kinase activity of the protein, therefore targeting LRRK2 kinase activity is a promising therapeutic approach. Phosphorylation at S935 of LRRK2 and of its Rab GTPase substrates have proven very useful biomarkers to monitor its kinase activity. Complementary to these approaches autophosphorylation of LRRK2 can be used as a direct kinase activity readout but to date detection of autophosphorylation at endogenous levels in vivo has been limited. We developed a fractionation-based enrichment method to successfully detect endogenous S1292 LRRK2 autophosphorylation in mouse tissues and highlight S1292 as a physiological readout candidate for LRRK2 kinase activity in vivo...
2018: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/29707191/environmental-and-genetic-variables-influencing-mitochondrial-health-and-parkinson-s-disease-penetrance
#9
REVIEW
Alessandra Zanon, Peter P Pramstaller, Andrew A Hicks, Irene Pichler
There is strong evidence that impairment of mitochondrial function plays a key role in the pathogenesis of PD. The two key PD genes related to mitochondrial function are Parkin ( PARK2 ) and PINK1 ( PARK6 ), and also mutations in several other PD genes, including SNCA , LRRK2 , DJ1 , CHCHD2 , and POLG , have been shown to induce mitochondrial stress. Many mutations are clearly pathogenic in some patients while carriers of other mutations either do not develop the disease or show a delayed onset, a phenomenon known as reduced penetrance...
2018: Parkinson's Disease
https://www.readbyqxmd.com/read/29705795/leucine-rich-repeat-kinase-2-in-parkinson-s-disease-updated-from-pathogenesis-to-potential-therapeutic-target
#10
Jinhua Chen, Ying Chen, Jiali Pu
BACKGROUND: Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. SUMMARY: Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment...
April 27, 2018: European Neurology
https://www.readbyqxmd.com/read/29705653/lrrk2-associated-parkinson-s-disease-patients-have-better-stereopsis-than-idiopathic-parkinson-disease
#11
Liang Sun, Piu Chan
OBJECTIVES: Visual dysfunctions are frequent and have several manifestations in idiopathic Parkinson's disease (PD). However, the characteristics of these complications in LRRK2 (leucine-rich kinase 2)-associated PD patients still lack systematic research. The purpose of this study is to assess visual functions of LRRK2-associated PD patients. PATIENTS AND METHODS: Twenty-five (25) PD patients with LRRK2 R1628P and G2385R variants were included in the study and compared to 28 PD patients without these variants and 28 age-matched healthy controls...
April 22, 2018: Clinical Neurology and Neurosurgery
https://www.readbyqxmd.com/read/29700116/comparative-analysis-of-parkinson-s-disease-associated-genes-reveals-altered-survival-and-bioenergetics-of-parkin-deficient-dopamine-neurons-in-mice
#12
Nicolas Giguere, Consiglia Pacelli, Caroline Saumure, Marie-Josee Bourque, Diana Matheoud, Daniel Levesque, Ruth S Slack, David S Park, Louis-Eric Trudeau
Many mutations in genes encoding proteins such as parkin, PTEN-induced putative kinase 1 (PINK1), protein deglycase DJ-1 (DJ-1 or PARK7), leucine-rich repeat kinase 2 (LRRK2), and α-synuclein have been linked to familial forms of Parkinson's disease (PD). The consequences of these mutations, such as altered mitochondrial function and pathological protein aggregation, are starting to be better understood. However, little is known about the mechanisms explaining why alterations in such diverse cellular mechanisms lead to the selective loss of dopamine (DA) neurons in the substantia nigra (SNc) in the brain of individuals with PD...
April 26, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29680709/parkinson-s-disease-like-burst-firing-activity-in-subthalamic-nucleus-induced-by-aav-%C3%AE-synuclein-is-normalized-by-lrrk2-modulation
#13
Michael Aagaard Andersen, Kenneth Vielsted Christensen, Lassina Badolo, Garrick Paul Smith, Ross Jeggo, Poul Henning Jensen, Kathrine Just Andersen, Florence Sotty
Parkinson's disease (PD) affects motor function through degenerative processes and synaptic transmission impairments in the basal ganglia. None of the treatments available delays or stops the progression of the disease. While α-synuclein pathological accumulation represents a hallmark of the disease in its idiopathic form, leucine rich repeat kinase 2 (LRRK2) is genetically associated with familial and sporadic forms of PD. The genetic information suggests that LRRK2 kinase activity plays a role in the pathogenesis of the disease...
April 19, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29666431/crohn-s-and-parkinson-disease-is-lrrk2-lurking-around-the-corner
#14
Pascal Derkinderen, Michel Neunlist
No abstract text is available yet for this article.
April 17, 2018: Nature Reviews. Gastroenterology & Hepatology
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
#15
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
#16
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/29622645/lrrk2-kinase-in-parkinson-s-disease
#17
Dario R Alessi, Esther Sammler
No abstract text is available yet for this article.
April 6, 2018: Science
https://www.readbyqxmd.com/read/29603409/application-of-the-movement-disorder-society-prodromal-criteria-in-healthy-g2019s-lrrk2-carriers
#18
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/29593234/case-control-analysis-of-lrrk2-protective-variants-in-essential-tremor
#19
Adeline S L Ng, Ebonne Y L Ng, Yi Jayne Tan, Kumar M Prakash, Wing Lok Au, Louis C S Tan, Eng-King Tan
Co-existence of Parkinson's disease (PD) and essential tremor (ET) may reflect overlapping pathophysiology underlying both conditions. Furthermore, PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations may present with ET-like features, suggesting the possibility of common genetic underpinnings. Two common LRRK2 variants, R1398H and N551K, have been shown to be protective in multiple PD cohorts. We hypothesized that R1398H and N551K may show a similar effect in ET. In a case-control study involving 3198 subjects (2680 controls and 518 ET cases), R1398H was detected in 16...
March 28, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29588215/discovery-of-4-ethoxy-7h-pyrrolo-2-3-d-pyrimidin-2-amines-as-potent-selective-and-orally-bioavailable-lrrk2-inhibitors
#20
Xiao Ding, Luigi Piero Stasi, Ming-Hsun Ho, Baowei Zhao, Hailong Wang, Kai Long, Qiongfeng Xu, Yingxia Sang, Changhui Sun, Huan Hu, Haihua Yu, Zehong Wan, Lizhen Wang, Colin Edge, Qian Liu, Yi Li, Kelly Dong, Xiaoming Guan, F David Tattersall, Alastair D Reith, Feng Ren
Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson's disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome...
March 19, 2018: Bioorganic & Medicinal Chemistry Letters
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