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Leucine repeat rich kinase 2

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https://www.readbyqxmd.com/read/28071824/heart-rate-variability-in-leucine-rich-repeat-kinase-2-associated-parkinson-s-disease
#1
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
#2
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
#3
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/28003339/lrguk1-is-part-of-a-multiprotein-complex-required-for-manchette-function-and-male-fertility
#4
Hidenobu Okuda, Kathleen DeBoer, Anne E O'Connor, D Jo Merriner, Duangporn Jamsai, Moira K O'Bryan
Infertility occurs in 1 in 20 young men and is idiopathic in origin in most. We have reported that the leucine-rich repeat (LRR) and guanylate kinase-like domain containing, isoform (LRGUK)-1 is essential for sperm head shaping, via the manchette, and the initiation of sperm tail growth from the centriole/basal body, and thus, male fertility. Within this study we have used a yeast 2-hybrid screen of an adult testis library to identify LRGUK1-binding partners, which were then validated with a range of techniques...
December 21, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27951586/nlrc3-is-an-inhibitory-sensor-of-pi3k-mtor-pathways-in-cancer
#5
Rajendra Karki, Si Ming Man, R K Subbarao Malireddi, Sannula Kesavardhana, Qifan Zhu, Amanda R Burton, Bhesh Raj Sharma, Xiaopeng Qi, Stephane Pelletier, Peter Vogel, Philip Rosenstiel, Thirumala-Devi Kanneganti
NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains...
December 12, 2016: Nature
https://www.readbyqxmd.com/read/27943591/effects-of-lrrk2-inhibitors-on-nigrostriatal-dopaminergic-neurotransmission
#6
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
#7
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/27925204/rabs-membrane-dynamics-and-parkinson-s-disease
#8
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/27923613/an-arabidopsis-thaliana-receptor-dead-kinase1-rdk1-gene-functions-as-a-positive-regulator-in-plant-responses-to-aba
#9
Dhinesh Kumar, Ritesh Kumar, Dongwon Baek, Tae-Kyung Hyun, Woo Sik Chung, Dae-Jin Yun, Jae-Yean Kim
Abscisic acid (ABA) is a major phytohormone involved in important stress-related and developmental plant processes. Membrane-delimited ABA signal transduction plays an important role in early ABA signaling, but the molecular mechanisms connecting core signaling components to the plasma membrane (PM) are unclear. Plants have evolved a large number of receptor-like kinases (RLKs) to modulate diverse biological processes by perceiving extracellular stimuli and activating downstream signaling responses. Here, a putative leucine-rich repeat (LRR)-RLK gene named RECEPTOR DEAD KINASE1 (AtRDK1) was identified and characterized in Arabidopsis thaliana...
December 3, 2016: Molecular Plant
https://www.readbyqxmd.com/read/27920157/two-serk-receptor-like-kinases-interact-with-ems1-to-control-anther-cell-fate-determination
#10
Zhiyong Li, Yao Wang, Jian Huang, Nagib Ahsan, Gabriel Biener, Joel Paprocki, Jay J Thelen, Valerica Raicu, Dazhong Zhao
Cell signaling pathways mediated by leucine-rich repeat receptor-like kinases (LRR-RLKs) are essential for plant growth, development, and defense. The EMS1 (EXCESS MICROSPOROCYTES1) LRR-RLK and its small protein ligand TPD1 (TAPETUM DETERMINANT1) play a fundamental role in somatic and reproductive cell differentiation during early anther development in Arabidopsis (Arabidopsis thaliana). However, it is unclear whether other cell surface molecules serve as coregulators of EMS1. Here, we show that SERK1 (SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE1) and SERK2 LRR-RLKs act redundantly as coregulatory and physical partners of EMS1...
January 2017: Plant Physiology
https://www.readbyqxmd.com/read/27913672/first-model-of-dimeric-lrrk2-the-challenge-of-unrevealing-the-structure-of-a-multidomain-parkinson-s-associated-protein
#11
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
#12
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
https://www.readbyqxmd.com/read/27913670/screening-for-chemical-modulators-for-lrrk2
#13
REVIEW
Heather Mortiboys
After the discovery of leucine-rich repeat kinase 2 (LRRK2) as a risk factor for sporadic Parkinson's disease (PD) and mutations in LRRK2 as a cause of some forms of familial PD, there has been substantial interest in finding chemical modulators of LRRK2 function. Most of the pathogenic mutations in LRRK2 are within the enzymatic cores of the protein; therefore, many screens have focused on finding chemical modulators of this enzymatic activity. There are alternative screening approaches that could be taken to investigate compounds that modulate LRRK2 cellular functions...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913669/the-unconventional-g-protein-cycle-of-lrrk2-and-roco-proteins
#14
REVIEW
Susanne Terheyden, Laura M Nederveen-Schippers, Arjan Kortholt
Mutations in the human leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of hereditary Parkinson's disease (PD). LRRK2 belongs to the Roco family of proteins, which are characterized by the presence of a Ras of complex proteins domain (Roc), a C-terminal of Roc domain (COR) and a kinase domain. Despite intensive research, much remains unknown about activity and the effect of PD-associated mutations. Recent biochemical and structural studies suggest that LRRK2 and Roco proteins are noncanonical G-proteins that do not depend on guanine nucleotide exchange factors or GTPase-activating proteins for activation...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913668/cellular-functions-of-lrrk2-implicate-vesicular-trafficking-pathways-in-parkinson-s-disease
#15
REVIEW
Mark R Cookson
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, associated with Parkinson's disease, have been shown to affect intracellular trafficking pathways in a variety of cells and organisms. An emerging theme is that LRRK2 can bind to multiple membranous structures in cells, and several recent studies have suggested that the Rab family of small GTPases might be important in controlling the recruitment of LRRK2 to specific cellular compartments. Once localized to membranes, LRRK2 then influences downstream events, evidenced by changes in the autophagy-lysosome pathway...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27911006/lrrk2-levels-and-phosphorylation-in-parkinson-s-disease-brain-and-cases-with-restricted-lewy-bodies
#16
Nicolas Dzamko, Amanda M Gysbers, Rina Bandopadhyay, Marc F Bolliger, Akiko Uchino, Ye Zhao, Masaki Takao, Sandrine Wauters, Wilma D J van de Berg, Junko Takahashi-Fujigasaki, R Jeremy Nichols, Janice L Holton, Shigeo Murayama, Glenda M Halliday
BACKGROUND: Leucine rich repeat kinase 2 (LRRK2) is a promising target for the treatment of Parkinson's disease; however, little is known about the expression of LRRK2 in human brain and if/how LRRK2 protein levels are altered in Parkinson's disease. OBJECTIVES: We measured the protein levels of LRRK2 as well as its phosphorylation on serines 910, 935, and 973 in the postmortem brain tissue of Parkinson's disease patients and aged controls with and without Lewy bodies...
December 2, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27909054/identification-of-a-substrate-selective-exosite-within-the-metalloproteinase-anthrax-lethal-factor
#17
Allison B Goldberg, Eunice Cho, Chad J Miller, Hua Jane Lou, Benjamin E Turk
The metalloproteinase anthrax lethal factor (LF) is secreted by Bacillus anthracis to promote disease virulence through disruption of host signaling pathways. LF is a highly specific protease, exclusively cleaving mitogen-activated protein kinase kinases (MKKs) and rodent NACHT leucine-rich repeat and pyrin domain containing protein 1B (NLRP1B). How LF achieves such restricted substrate specificity is not understood. Previous studies have suggested the existence of an exosite interaction between LF and MKKs that promotes cleavage efficiency and specificity...
December 1, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27903237/leucine-rich-repeat-kinase-2-lrrk2-regulates-%C3%AE-synuclein-clearance-in-microglia
#18
Tatsunori Maekawa, Toshikuni Sasaoka, Sadahiro Azuma, Takafumi Ichikawa, Heather L Melrose, Matthew J Farrer, Fumiya Obata
BACKGROUND: α-Synuclein (αSYN) has been genetically implicated in familial and sporadic Parkinson's disease (PD), and is associated with disease susceptibility, progression and pathology. Excess amounts of αSYN are toxic to neurons. In the brain, microglial αSYN clearance is closely related to neuronal survival. Leucine-rich repeat kinase 2 (LRRK2) is the one of the other genes implicated in familial and sporadic PD. While LRRK2 is known to be expressed in microglia, its true function remains to be elucidated...
November 30, 2016: BMC Neuroscience
https://www.readbyqxmd.com/read/27890708/fbxl18-targets-lrrk2-for-proteasomal-degradation-and-attenuates-cell-toxicity
#19
Xiaodong Ding, Sandeep K Barodia, Lisha Ma, Matthew S Goldberg
Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of familial Parkinson's disease (PD) and LRRK2 polymorphisms are associated with increased risk for idiopathic PD. However, the molecular mechanisms by which these mutations cause PD remain uncertain. In vitro studies indicate that disease-linked mutations in LRRK2 increase LRRK2 kinase activity and LRRK2-mediated cell toxicity. Identifying LRRK2-interacting proteins and determining their effects on LRRK2 are important for understanding LRRK2 function and for delineating the pathophysiological mechanisms of LRRK2 mutations...
February 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/27884160/the-d-domain-of-lrrc4-anchors-erk1-2-in-the-cytoplasm-and-competitively-inhibits-mek-erk-activation-in-glioma-cells
#20
Zeyou Wang, Qin Guo, Rong Wang, Gang Xu, Peiyao Li, Yingnan Sun, Xiaoling She, Qiang Liu, Qiong Chen, Zhibin Yu, Changhong Liu, Jing Xiong, Guiyuan Li, Minghua Wu
BACKGROUND: As a well-characterized key player in various signal transduction networks, extracellular-signal-regulated kinase (ERK1/2) has been widely implicated in the development of many malignancies. We previously found that Leucine-rich repeat containing 4 (LRRC4) was a tumor suppressor and a negative regulator of the ERK/MAPK pathway in glioma tumorigenesis. However, the precise molecular role of LRRC4 in ERK signal transmission is unclear. METHODS: The interaction between LRRC4 and ERK1/2 was assessed by co-immunoprecipitation and GST pull-down assays in vivo and in vitro...
November 25, 2016: Journal of Hematology & Oncology
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