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https://www.readbyqxmd.com/read/28529829/connecting-ca-2-and-lysosomes-to-parkinson-disease
#1
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
#2
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
#3
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
#4
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
#5
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 Results Male (LRRK2-G2019S) LRRK2-Tg mice showed impairments in the early portion of the Two-day radial arm water maze acquisition trial as well as in the reversal learning on the third day...
May 6, 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
#6
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
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/28453723/gtp-binding-regulates-cellular-localization-of-parkinso%C3%A5-s-disease-associated-lrrk2
#11
Marian Blanca Ramírez, Antonio Jesús Lara Ordóñez, Elena Fdez, Jesús Madero-Pérez, Adriano Gonnelli, Matthieu Drouyer, Marie-Christine Chartier-Harlin, Jean-Marc Taymans, Luigi Bubacco, Elisa Greggio, Sabine Hilfiker
Mutations in LRRK2 comprise the most common cause of familial Parkinsońs disease (PD), and sequence variants modify risk for sporadic PD. Previous studies indicate that LRRK2 interacts with microtubules and alters microtubule-mediated vesicular transport processes. However, the molecular determinants within LRRK2 required for such interactions have remained unknown. Here we report that most pathogenic LRRK2 mutants cause relocalization of LRRK2 to filamentous structures which colocalize with a subset of microtubules, and an identical relocalization is seen upon pharmacological LRRK2 kinase inhibition...
April 26, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28445933/the-long-noncoding-rna-hotair-promotes-parkinson-s-disease-by-upregulating-lrrk2-expression
#12
Sheng Wang, Xuan Zhang, Yuanyuan Guo, Han Rong, Tiebang Liu
Long noncoding RNAs (lncRNAs) have emerged recently as a new class of genes that regulate cellular processes. HOTAIR (Hox transcript antisense intergenic RNA), an approximately 2.2 kb long noncoding RNA transcribed from the HOXC locus, is upregulated in various diseases. However, the role of HOTAIR in Parkinson's disease (PD) remains unclear. A mouse model of PD was developed by intraperitoneal injection of MPTP. The expression of HOTAIR and LRRK2 were detected in the PD mice and in human neuroblastoma cell lines SH-SY5Y pretreated with MPP+...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28443359/targeting-lrrk2-in-parkinson-s-disease-an-update-on-recent-developments
#13
Sharon L Chan, Eng-King Tan
LRRK2 research has progressed significantly in recent years with more reports of LRRK2 interactors and the development of more specific and sophisticated LRRK2 kinase inhibitors. Identification of bone fide LRRK2 substrates will provide new therapeutic targets in LRRK2-linked Parkinson's disease (PD). Areas covered: This review aims to put current LRRK2 research into perspective. Beginning with recent LRRK2 mammalian models employed for in vivo validation of LRRK2 substrates, followed by updates on reported LRRK2 interactors and their inferred mechanisms...
May 15, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28420983/increased-oxidative-stress-markers-in-cerebrospinal-fluid-from-healthy-subjects-with-parkinson-s-disease-associated-lrrk2-gene-mutations
#14
David A Loeffler, Andrea C Klaver, Mary P Coffey, Jan O Aasly, Peter A LeWitt
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of inherited Parkinson's disease (PD). The most common PD-associated LRRK2 mutation, G2019S, induces increased production of reactive oxygen species in vitro. We therefore hypothesized that individuals with PD-associated LRRK2 mutations might have increased concentrations of oxidative stress markers and/or decreased total antioxidant capacity (TAC) in their cerebrospinal fluid (CSF). We measured two oxidative stress markers, namely 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostane (8-ISO), and TAC in CSF from LRRK2 mutation-bearing PD patients (LRRK2 PD = 19), sporadic PD patients (sPD = 31), and healthy control subjects with or without these mutations (LRRK2 CTL = 30, CTL = 27)...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28419651/reply-letter-to-does-motor-cortex-plasticity-depend-on-the-type-of-mutation-in-the-lrrk2-gene
#15
REVIEW
Francesco Di Lorenzo, Viviana Ponzo, Livia Brusa, Carlo Caltagirone, Giacomo Koch
No abstract text is available yet for this article.
April 17, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28414642/disease-progression-in-lrrk2-parkinsonism
#16
Marios Politis
No abstract text is available yet for this article.
May 2017: Lancet Neurology
https://www.readbyqxmd.com/read/28408230/discovery-of-lrrk2-inhibitors-by-using-an-ensemble-of-virtual-screening-methods
#17
Emanuela Gancia, Marcel De Groot, Brenda Burton, David E Clark
In this paper, we present the results of a ligand- and structure-based virtual screen targeting LRRK2, a kinase that has been implicated in Parkinson's disease. For the ligand-based virtual screen, the structures of 12 competitor compounds were used as queries for a variety of 2D and 3D searches. The structure-based virtual screen relied on homology models of LRRK2, as no X-ray structure is currently available in the public domain. From the virtual screening, 662 compounds were purchased, of which 35 showed IC50 values below 10μM in wild-type and/or mutant LRRK2 (a hit rate of 5...
April 2, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28407521/genetic-or-pharmacological-activation-of-the-drosophila-pgc-1%C3%AE-ortholog-spargel-rescues-the-disease-phenotypes-of-genetic-models-of-parkinson-s-disease
#18
Chee-Hoe Ng, Adeline H Basil, Liting Hang, Royston Tan, Kian-Leong Goh, Sharon O'Neill, Xiaodong Zhang, Fengwei Yu, Kah-Leong Lim
Despite intensive research, the etiology of Parkinson's disease (PD) remains poorly understood and the disease remains incurable. However, compelling evidence gathered over decades of research strongly support a role for mitochondrial dysfunction in PD pathogenesis. Related to this, PGC-1α, a key regulator of mitochondrial biogenesis, has recently been proposed to be an attractive target for intervention in PD. Here, we showed that silencing of expression of the Drosophila PGC-1α ortholog spargel results in PD-related phenotypes in flies and also seem to negate the effects of AMPK activation, which we have previously demonstrated to be neuroprotective, that is, AMPK-mediated neuroprotection appears to require PGC-1α...
March 18, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28406934/dat-spect-assessment-depicts-dopamine-depletion-among-asymptomatic-g2019s-lrrk2-mutation-carriers
#19
COMPARATIVE STUDY
Moran Artzi, Einat Even-Sapir, Hedva Lerman Shacham, Avner Thaler, Avi Orr Urterger, Susan Bressman, Karen Marder, Talma Hendler, Nir Giladi, Dafna Ben Bashat, Anat Mirelman
Identification of early changes in Dopamine-Transporter (DaT) SPECT imaging expected in the prodromal phase of Parkinson's disease (PD), are usually overlooked. Carriers of the G2019S LRRK2 mutation are known to be at high risk for developing PD, compared to non-carriers. In this work we aimed to study early changes in Dopamine uptake in non-manifesting PD carriers (NMC) of the G2019S LRRK2 mutation using quantitative DaT-SPECT analysis and to examine the potential for early prediction of PD. Eighty Ashkenazi-Jewish subjects were included in this study: eighteen patients with PD; thirty-one NMC and thirty-one non-manifesting non-carriers (NMNC)...
2017: PloS One
https://www.readbyqxmd.com/read/28395805/generation-of-a-human-induced-pluripotent-stem-cell-ipsc-line-carrying-the-parkinson-s-disease-linked-lrrk2-variant-s1647t
#20
Dongrui Ma, Shin Hui Ng, Li Zeng, Yi Zhao, Eng King Tan
Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 64-year old male Parkinson's disease (PD) patient with S1647T variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model will be useful for further function studies and therapeutic screening...
January 2017: Stem Cell Research
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