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https://www.readbyqxmd.com/read/28235153/distinctive-genomic-signature-of-neural-and-intestinal-organoids-from-familial-parkinson-s-disease-patient-derived-induced-pluripotent-stem-cells
#1
Mi-Young Son, Hyuna Sim, Ye Seul Son, Kwang Bo Jung, Mi-Ok Lee, Jung-Hwa Oh, Sun-Ku Chung, Cho-Rok Jung, Janghwan Kim
AIMS: The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic cause of Parkinson's disease (PD). There is compelling evidence that PD is not only a brain disease but also a gastrointestinal disorder; nonetheless, its pathogenesis remains unclear. We aimed to develop human neural and intestinal tissue models of PD patients harboring an LRRK2 mutation to understand the link between LRRK2 and PD pathology by investigating the gene expression signature. METHODS: We generated PD patient-specific induced pluripotent stem cells (iPSCs) carrying an LRRK2 G2019S mutation (LK2GS) and then differentiated into three-dimensional (3D) human neuroectodermal spheres (hNESs) and human intestinal organoids (hIOs)...
February 24, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28224253/lrrk2-expression-in-the-enteric-nervous-system-ensuring-its-significance
#2
EDITORIAL
Pascal Derkinderen
No abstract text is available yet for this article.
February 21, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/28223019/synthesis-of-11-c-hg-10-102-01-as-a-new-potential-pet-agent-for-imaging-of-lrrk2-enzyme-in-parkinson-s-disease
#3
Min Wang, Mingzhang Gao, Zhidong Xu, Qi-Huang Zheng
The reference standard (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (HG-10-102-01) and its precursor (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-hydroxyphenyl)(morpholino)methanone (desmethyl-HG-10-102-01) were synthesized from 2,4,5-trichloropyrimide and 3-methoxy-4-nitrobenzoic acid with overall chemical yield 49% in four steps and 14% in five steps, respectively. The target tracer (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-[(11)C]methoxyphenyl)(morpholino)methanone ([(11)C]HG-10-102-01) was prepared from the precursor desmethyl-HG-10-102-01 with [(11)C]CH3OTf through O-[(11)C]methylation and isolated by HPLC combined with SPE in 45-55% radiochemical yield, based on [(11)C]CO2 and decay corrected to end of bombardment (EOB)...
February 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28222538/vps35-the-retromer-complex-and-parkinson-s-disease
#4
Erin T Williams, Xi Chen, Darren J Moore
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene encoding a core component of the retromer complex, have recently emerged as a new cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, AspD620Asn (D620N), has so far been unambiguously identified to cause PD in multiple individuals and families worldwide. The exact molecular mechanism(s) by which VPS35 mutations induce progressive neurodegeneration in PD are not yet known. Understanding these mechanisms, as well as the perturbed cellular pathways downstream of mutant VPS35, is important for the development of appropriate therapeutic strategies...
February 8, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28220571/genetic-risk-factors-for-cognitive-decline-in-parkinson-s-disease-a-review-of-the-literature
#5
REVIEW
E S Fagan, L Pihlstrøm
Parkinson's disease is a highly heterogeneous disorder, where genetic factors are likely to contribute to clinical variability, including susceptibility to cognitive impairment and dementia. Monogenic forms of parkinsonism show distinct cognitive profiles, yet less is known about the impact of common genetic variants on cognition in sporadic Parkinson's disease. In a systematic review of the literature, the current results from genetic association studies of cognitive outcomes are summarized and prospects and challenges for future studies are discussed...
February 21, 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/28213071/pla2g6-accumulates-in-lewy-bodies-in-park14-and-idiopathic-parkinson-s-disease
#6
Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi
The histopathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is the occurrence of insoluble fibrillary aggregates known as Lewy bodies, in which phosphorylated α-synuclein (α-syn) is a major component. To date, familial PD-linked gene products, including α-syn, parkin, PINK-1, DJ-1 and LRRK2, are known to be involved in Lewy body formation. Phospholipase A2, group VI (PLA2G6) is the causative gene for PARK14-linked parkinsonism (PARK14), a familial form of juvenile-onset dystonia parkinsonism...
February 14, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28205494/language-deficits-as-a-preclinical-window-into-parkinson-s-disease-evidence-from-asymptomatic-parkin-and-dardarin-mutation-carriers
#7
Adolfo M García, Lucas Sedeño, Natalia Trujillo, Yamile Bocanegra, Diana Gomez, David Pineda, Andrés Villegas, Edinson Muñoz, William Arias, Agustín Ibáñez
OBJECTIVES: The worldwide spread of Parkinson's disease (PD) calls for sensitive and specific measures enabling its early (or, ideally, preclinical) detection. Here, we use language measures revealing deficits in PD to explore whether similar disturbances are present in asymptomatic individuals at risk for the disease. METHODS: We administered executive, semantic, verb-production, and syntactic tasks to sporadic PD patients, genetic PD patients with PARK2 (parkin) or LRRK2 (dardarin) mutation, asymptomatic first-degree relatives of the latter with similar mutations, and socio-demographically matched controls...
February 2017: Journal of the International Neuropsychological Society: JINS
https://www.readbyqxmd.com/read/28202711/structural-interface-between-lrrk2-and-14-3-3-protein
#8
Loes Stevers, Rens de Vries, Richard Doveston, Lech-Gustav Milroy, Luc Brunsveld, Christian Ottmann
Binding of 14-3-3 proteins to LRRK2 is known to be impaired by a number of Parkinson's disease (PD)-relevant mutations. Abrogation of this interaction is connected to enhanced LRRK2 kinase activity which in turn is implicated in increased ubiquitination of LRRK2, accumulation of LRRK2 into inclusion bodies and reduction of neurite length. Hence, the interaction between 14-3-3 and LRRK2 is of significant interest as a possible drug target for the treatment of PD. However, LRRK2 possesses multiple sites that upon phosphorylation can bind to 14-3-3, thus rendering the interaction relatively complex...
February 15, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28202680/cross-talk-between-lrrk2-and-pka-implication-for-parkinson-s-disease
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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/28168579/lrrk2-an-emerging-new-molecule-in-the-enteric-neuronal-system-that-quantitatively-regulates-neuronal-peptides-and-iga-in-the-gut
#18
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
#19
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/28158614/lrrk2-i2020t-functional-genetic-interactors-that-modify-eye-degeneration-and-dopaminergic-cell-loss-in-drosophila
#20
Paul C Marcogliese, Sameera Abuaish, Ghassan Kabbach, Elizabeth Abdel-Messih, Sarah Seang, Gang Li, Ruth S Slack, M Emdadul Haque, Katerina Venderova, David S Park
No abstract text is available yet for this article.
February 2, 2017: Human Molecular Genetics
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