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Leucine repeat rich kinase 2

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https://www.readbyqxmd.com/read/28202680/cross-talk-between-lrrk2-and-pka-implication-for-parkinson-s-disease
#1
REVIEW
Elisa Greggio, Luigi Bubacco, Isabella Russo
Evidence indicates that leucine-rich repeat kinase 2 (LRRK2) controls multiple processes in neurons and glia cells. Deregulated LRRK2 activity due to gene mutation represents the most common cause of autosomal dominant Parkinson's disease (PD). Protein kinase A (PKA)-mediated signaling is a key regulator of brain function. PKA-dependent pathways play an important role in brain homeostasis, neuronal development, synaptic plasticity, control of microglia activation and inflammation. On the other hand, a decline of PKA signaling was shown to contribute to the progression of several neurodegenerative diseases, including PD...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202674/lrrk2-detection-in-human-biofluids-potential-use-as-a-parkinson-s-disease-biomarker
#2
REVIEW
Jean-Marc Taymans, Eugénie Mutez, Matthieu Drouyer, William Sibran, Marie-Christine Chartier-Harlin
Leucine-rich repeat kinase 2 (LRRK2) is a complex signalling protein that is a key therapeutic target, particularly in Parkinson's disease (PD). In addition, there is now evidence showing that LRRK2 expression and phosphorylation levels have potential as markers of disease or target engagement. Indeed, reports show increases in LRRK2 protein levels in the prefrontal cortex of PD patients relative to controls, suggesting that increase in total LRRK2 protein expression is correlated with disease progression. LRRK2 phosphorylation levels are reduced in experimental systems for most disease mutants, and LRRK2 is also rapidly dephosphorylated upon LRRK2 inhibitor treatment, considered potential therapeutics...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202670/mechanisms-of-lrrk2-dependent-neurodegeneration-role-of-enzymatic-activity-and-protein-aggregation
#3
REVIEW
Md Shariful Islam, Darren J Moore
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson's disease (PD) with autosomal dominant inheritance. Accordingly, LRRK2 has emerged as a promising therapeutic target for disease modification in PD. Since the first discovery of LRRK2 mutations some 12 years ago, LRRK2 has been the subject of intense investigation. It has been established that LRRK2 can function as a protein kinase, with many putative substrates identified, and can also function as a GTPase that may serve in part to regulate kinase activity...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202669/the-lrrk2-macroautophagy-axis-and-its-relevance-to-parkinson-s-disease
#4
REVIEW
Claudia Manzoni
A wide variety of different functions and an impressive array of interactors have been associated with leucine-rich repeat kinase 2 (LRRK2) over the years. Here, I discuss the hypothesis that LRRK2 may be capable of interacting with different proteins at different times and places, therefore, controlling a plethora of diverse functions based on the different complexes formed. Among these, I will then focus on macroautophagy in the general context of the endolysosomal system. First, the relevance of autophagy in Parkinson's disease will be evaluated giving a brief overview of all the relevant Parkinson's disease genes; then, the association of LRRK2 with macroautophagy and the endolysosomal pathway will be analyzed based on the supporting literature...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202668/cellular-effects-mediated-by-pathogenic-lrrk2-homing-in-on-rab-mediated-processes
#5
REVIEW
Jesús Madero-Pérez, Elena Fdez, Belén Fernández, Antonio Jesús Lara Ordóñez, Marian Blanca Ramírez, María Romo Lozano, Pilar Rivero-Ríos, Sabine Hilfiker
Leucine-rich repeat kinase 2 (LRRK2) is a key player in the pathogenesis of Parkinson's disease. Mutations in LRRK2 are associated with increased kinase activity that correlates with cytotoxicity, indicating that kinase inhibitors may comprise promising disease-modifying compounds. However, before embarking on such strategies, detailed knowledge of the cellular deficits mediated by pathogenic LRRK2 in the context of defined and pathologically relevant kinase substrates is essential. LRRK2 has been consistently shown to impair various intracellular vesicular trafficking events, and recent studies have shown that LRRK2 can phosphorylate a subset of proteins that are intricately implicated in those processes...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202667/lrrk2-from-kinase-to-gtpase-to-microtubules-and-back
#6
REVIEW
Marian Blanca Ramírez, Antonio Jesús Lara Ordóñez, Elena Fdez, Sabine Hilfiker
Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are intimately linked to both familial and sporadic Parkinson's disease. LRRK2 is a large protein kinase able to bind and hydrolyse GTP. A wealth of in vitro studies have established that the distinct pathogenic LRRK2 mutants differentially affect those enzymatic activities, either causing an increase in kinase activity without altering GTP binding/GTP hydrolysis, or displaying no change in kinase activity but increased GTP binding/decreased GTP hydrolysis...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202666/lrrk2-in-peripheral-and-central-nervous-system-innate-immunity-its-link-to-parkinson-s-disease
#7
REVIEW
Heyne Lee, William S James, Sally A Cowley
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are found in familial and idiopathic cases of Parkinson's disease (PD), but are also associated with immune-related disorders, notably Crohn's disease and leprosy. Although the physiological function of LRRK2 protein remains largely elusive, increasing evidence suggests that it plays a role in innate immunity, a process that also has been implicated in neurodegenerative diseases, including PD. Innate immunity involves macrophages and microglia, in which endogenous LRRK2 expression is precisely regulated and expression is strongly up-regulated upon cell activation...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202665/neuronal-death-signaling-pathways-triggered-by-mutant-lrrk2
#8
REVIEW
Hardy J Rideout
Autosomal dominantly inherited mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. While considerable progress has been made in understanding its function and the many different cellular activities in which it participates, a clear understanding of the mechanism(s) of the induction of neuronal death by mutant forms of LRRK2 remains elusive. Although several in vivo models have documented the progressive loss of dopaminergic neurons of the substantia nigra, more complete interrogations of the modality of neuronal death have been gained from cellular models...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202664/lrrk2-mouse-models-dissecting-the-behavior-striatal-neurochemistry-and-neurophysiology-of-pd-pathogenesis
#9
REVIEW
Mattia Volta, Heather Melrose
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD), resembling the sporadic disorder. Intensive effort has been directed toward LRRK2 mouse modeling and investigation, aimed at reproducing the human disease to inform mechanistic studies of pathogenesis and design of neuroprotective therapies. The physiological function of LRRK2 is still under exploration, but a clear role in striatal neurophysiology and animal behavior has emerged. Alterations in LRRK2 impair dopamine (DA) transmission, regulation and signaling, in addition to corticostriatal synaptic plasticity...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28186666/impaired-intracortical-transmission-in-g2019s-leucine-rich-repeat-kinase-parkinson-patients
#10
Viviana Ponzo, Francesco Di Lorenzo, Livia Brusa, Tommaso Schirinzi, Stefania Battistini, Claudia Ricci, Manolo Sambucci, Carlo Caltagirone, Giacomo Koch
OBJECTIVES: A mutation in leucine-rich repeat kinase 2 is the most common cause of hereditary Parkinson's disease (PD), yet the neural mechanisms and the circuitry potentially involved are poorly understood. METHODS: We used different transcranial magnetic stimulation protocols to explore in the primary motor cortex the activity of intracortical circuits and cortical plasticity (long-term potentiation) in patients with the G2019S leucine-rich repeat kinase 2 gene mutation when compared with idiopathic PD patients and age-matched healthy subjects...
February 10, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28168579/lrrk2-an-emerging-new-molecule-in-the-enteric-neuronal-system-that-quantitatively-regulates-neuronal-peptides-and-iga-in-the-gut
#11
Tatsunori Maekawa, Hitomi Shimayama, Hiromichi Tsushima, Fumitaka Kawakami, Rei Kawashima, Makoto Kubo, Takafumi Ichikawa
BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) is a recently discovered molecule associated with familial and sporadic Parkinson's disease. It regulates many central neuronal functions such as cell proliferation, apoptosis, autophagy, and axonal extension. However, in contrast to the well-documented function of LRRK2 in central neurons, it is unclear whether LRRK2 is expressed in enteric neurons and affects the physiology of the gut. AIMS: By examining LRRK2-KO mice, this study investigated whether enteric neurons express LRRK2 and whether intestinal neuronal peptides and IgA are quantitatively changed...
February 6, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/28160489/sec16-in-conventional-and-unconventional-exocytosis-working-at-the-interface-of-membrane-traffic-and-secretory-autophagy
#12
REVIEW
Bor Luen Tang
Sec16 is classically perceived to be a scaffolding protein localized to the transitional endoplasmic reticulum (tER) or the ER exit sites (ERES), and has a conserved function in facilitating coat protein II (COPII) complex-mediated ER exit. Recent findings have however pointed towards a role for Sec16 in unconventional exocytosis of certain membrane proteins, such as the Cystic fibrosis transmembrane conductance regulator (CFTR) in mammalian cells, and possibly also α-integrin in certain contexts of Drosophila development...
February 4, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28131193/the-heterozygous-r1441c-mutation-of-leucine-rich-repeat-kinase-2-gene-in-a-chinese-patient-with-parkinson-disease-a-five-year-follow-up-and-literatures-review
#13
Fang Peng, Yi-Min Sun, Chen Chen, Su-Shan Luo, Da-Ke Li, Yi-Xuan Wang, Ke Yang, Feng-Tao Liu, Chuan-Tao Zuo, Zheng-Tong Ding, Yu An, Jian-Jun Wu, Jian Wang
BACKGROUND: Leucine-rich repeat kinase 2 gene (LRRK2) was recognized associated with both familial and sporadic Parkinson Disease (PD). Seven missense mutations (G2019S, R1441C, R1441G, R1441H, Y1699C, I2020T, N1437H) of it have been confirmed disease- causing. They were common among Caucasian PD patients, but rarely reported in Asian, especially in Chinese Han population. OBJECTIVES: We aimed to identify the frequencies of these seven mutations of LRRK2 in Chinese early-onset PD (EOPD) patients and analyze the phenotypes...
February 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28120865/leucine-rich-repeat-kinase-2-lrrk2-sensitive-na-k-atpase-activity-in-dendritic-cells
#14
Zohreh Hosseinzadeh, Yogesh Singh, Derya R Shimshek, Herman van der Putten, Carsten A Wagner, Florian Lang
Leucine-rich repeat kinase 2 (Lrrk2) has been implicated in the pathophysiology of Parkinson's disease. Lrrk2 is expressed in diverse cells including neurons and dendritic cells (DCs). In DCs Lrrk2 was shown to up-regulate Na(+)/Ca(2+)-exchanger activity. The elimination of Ca(2+) by Na(+)/Ca(2+) -exchangers requires maintenance of the Na(+) gradient by the Na(+)/K(+) -ATPase. The present study thus explored whether Lrrk2 impacts on Na(+)/K(+) -ATPase expression and function. To this end DCs were isolated from gene-targeted mice lacking Lrrk2 (Lrrk2(-/-)) and their wild-type littermates (Lrrk2(+/+))...
January 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28117607/leucine-rich-repeat-kinase-2-inhibitors-a-patent-review-2014-2016
#15
Paul Galatsis
Leucine-rich repeat kinase 2 (LRRK2) is a member of the Tyrosine Kinase-Like (TKL) branch of the kinome tree and is a multi-domain protein that includes GTPase and kinase activity. While genome-wide association studies (GWAS) has linked LRRK2 with Crohn's disease and leprosy, it has received the greatest attention due to it being implicated as one of the genetic loci associated with autosomal dominant inheritance in Parkinson's disease (PD). Areas covered: In this review, the small molecule patent literature from 2014-2016 with a focus on composition of matter and use patents was surveyed...
January 31, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28098219/combined-lrrk2-mutation-aging-and-chronic-low-dose-oral-rotenone-as-a-model-of-parkinson-s-disease
#16
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/28090684/predict-pd-an-online-approach-to-prospectively-identify-risk-indicators-of-parkinson-s-disease
#17
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...
February 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
#18
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
#19
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
#20
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...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
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