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Synuclein microglia

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https://www.readbyqxmd.com/read/29024008/immunization-with-%C3%AE-synuclein-grp94-reshapes-peripheral-immunity-and-suppresses-microgliosis-in-a-chronic-parkinsonism-model
#1
Javier Villadiego, Adahir Labrador-Garrido, Jaime M Franco, Magdalena Leal-Lasarte, Erwin J De Genst, Christopher M Dobson, David Pozo, Juan J Toledo-Aral, Cintia Roodveldt
Neuroinflammation mediated by chronically activated microglia, largely caused by abnormal accumulation of misfolded α-synuclein (αSyn) protein, is known to contribute to the pathophysiology of Parkinson's disease (PD). In this work, based on the immunomodulatory activities displayed by particular heat-shock proteins (HSPs), we tested a novel vaccination strategy that used a combination of αSyn and Grp94 (HSPC4 or Gp96) chaperone and a murine PD model. We used two different procedures, first, the adoptive transfer of splenocytes from αSyn/Grp94-immunized mice to recipient animals, and second, direct immunization with αSyn/Grp94, to study the effects in a chronic mouse MPTP-model of parkinsonism...
October 11, 2017: Glia
https://www.readbyqxmd.com/read/28921554/dj-1-deficiency-impairs-autophagy-and-reduces-alpha-synuclein-phagocytosis-by-microglia
#2
Yuval Nash, Eran Schmukler, Dorit Trudler, Ronit Pinkas-Kramarski, Dan Frenkel
Parkinson's disease (PD) is a progressive neurodegenerative disorder, of which 1% of the hereditary cases are linked to mutations in DJ-1, an oxidative stress sensor. The pathological hallmark of PD is intercellular inclusions termed Lewy Bodies, composed mainly of α-Synuclein (α-Syn) protein. Recent findings have shown that α-Syn can be transmitted from cell to cell, suggesting an important role of microglia, as the main scavenger cells of the brain, in clearing α-Syn. We previously reported that the knock down (KD) of DJ-1 in microglia increased cells' neurotoxicity to dopaminergic neurons...
September 16, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28918943/vagus-nerve-stimulation-improves-locomotion-and-neuronal-populations-in-a-model-of-parkinson-s-disease
#3
Ariana Q Farrand, Kristi L Helke, Rebecca A Gregory, Monika Gooz, Vanessa K Hinson, Heather A Boger
BACKGROUND: Parkinson's disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA) neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory markers, allowing improvement of LC targets, making it a potential PD therapeutic. OBJECTIVE: To assess therapeutic potential of VNS in a PD model...
August 24, 2017: Brain Stimulation
https://www.readbyqxmd.com/read/28903781/transmission-of-%C3%AE-synuclein-containing-erythrocyte-derived-extracellular-vesicles-across-the-blood-brain-barrier-via-adsorptive-mediated-transcytosis-another-mechanism-for-initiation-and-progression-of-parkinson-s-disease
#4
Junichi Matsumoto, Tessandra Stewart, Lifu Sheng, Na Li, Kristin Bullock, Ning Song, Min Shi, William A Banks, Jing Zhang
Parkinson's disease (PD) pathophysiology develops in part from the formation, transmission, and aggregation of toxic species of the protein α-synuclein (α-syn). Recent evidence suggests that extracellular vesicles (EVs) may play a vital role in the transport of toxic α-syn between brain regions. Moreover, increasing evidence has highlighted the participation of peripheral molecules, particularly inflammatory species, which may influence or exacerbate the development of PD-related changes to the central nervous system (CNS), although detailed characterization of these species remains to be completed...
September 13, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28900002/modeling-parkinson-s-disease-pathology-by-combination-of-fibril-seeds-and-%C3%AE-synuclein-overexpression-in-the-rat-brain
#5
Poonam Thakur, Ludivine S Breger, Martin Lundblad, Oi Wan Wan, Bengt Mattsson, Kelvin C Luk, Virginia M Y Lee, John Q Trojanowski, Anders Björklund
Although a causative role of α-synuclein (α-syn) is well established in Parkinson's disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson's disease by injecting human α-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human α-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration...
September 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28863860/discoidin-domain-receptor-inhibition-reduces-neuropathology-and-attenuates-inflammation-in-neurodegeneration-models
#6
Michaeline Hebron, Margo Peyton, Xiaoguang Liu, Xiaokong Gao, Ruochong Wang, Irina Lonskaya, Charbel E-H Moussa
The role of cell surface tyrosine kinase collagen-activated receptors known as discoidin domain receptors (DDRs) is unknown in neurodegenerative diseases. We detect up-regulation in DDRs level in post-mortem Alzheimer and Parkinson brains. Lentiviral shRNA knockdown of DDR1 and DDR2 reduces the levels of α-synuclein, tau, and β-amyloid and prevents cell loss in vivo and in vitro. DDR1 and DDR2 knockdown alters brain immunity and significantly reduces the level of triggering receptor expressed on myeloid cells (TREM)-2 and microglia...
October 15, 2017: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/28836226/the-ketone-body-%C3%AE-hydroxybutyrate-does-not-inhibit-synuclein-mediated-inflammasome-activation-in-microglia
#7
Vandana Deora, Eduardo A Albornoz, Kevin Zhu, Trent M Woodruff, Richard Gordon
Parkinson's disease (PD) is recognized as the most common neurodegenerative movement disorder and results in debilitating motor deficits. The accumulation and spread of neurotoxic synuclein aggregates in the form of Lewy bodies is a key pathological feature of PD. Chronic activation of the NLRP3 inflammasome by protein aggregates is emerging as a major pathogenic mechanism in progressive neurodegenerative disorders and is considered an important therapeutic target. Recently the ketone body, β-hydroxy butyrate (BHB), was shown to efficiently inhibit the NLRP3 inflammasome in macrophages, and in vivo models of inflammatory disease...
August 23, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28827786/excess-%C3%AE-synuclein-compromises-phagocytosis-in-ipsc-derived-macrophages
#8
Walther Haenseler, Federico Zambon, Heyne Lee, Jane Vowles, Federica Rinaldi, Galbha Duggal, Henry Houlden, Katrina Gwinn, Selina Wray, Kelvin C Luk, Richard Wade-Martins, William S James, Sally A Cowley
To examine the pathogenic role of α-synuclein (αS) in Parkinson's Disease, we have generated induced Pluripotent Stem Cell lines from early onset Parkinson's Disease patients with SNCA A53T and SNCA Triplication mutations, and in this study have differentiated them to PSC-macrophages (pMac), which recapitulate many features of their brain-resident cousins, microglia. We show that SNCA Triplication pMac, but not A53T pMac, have significantly increased intracellular αS versus controls and release significantly more αS to the medium...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28827536/cellular-internalization-of-alpha-synuclein-aggregates-by-cell-surface-heparan-sulfate-depends-on-aggregate-conformation-and-cell-type
#9
Elisabet Ihse, Hodaka Yamakado, Xander M van Wijk, Roger Lawrence, Jeffrey D Esko, Eliezer Masliah
Amyloid aggregates found in the brain of patients with neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are thought to spread to increasingly larger areas of the brain through a prion-like seeding mechanism. Not much is known about which cell surface receptors may be involved in the cell-to-cell transfer, but proteoglycans are of interest due to their well-known propensity to interact with amyloid aggregates. In this study, we investigated the involvement of plasma membrane-bound heparan and chondroitin sulfate proteoglycans in cellular uptake of aggregates consisting of α-synuclein, a protein forming amyloid aggregates in Parkinson's disease...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28774789/impaired-cbs-h2s-signaling-axis-contributes-to-mptp-induced-neurodegeneration-in-a-mouse-model-of-parkinson-s-disease
#10
Yu-Qing Yuan, Ya-Li Wang, Bao-Shi Yuan, Xin Yuan, Xiao-Ou Hou, Jin-Song Bian, Chun-Feng Liu, Li-Fang Hu
Hydrogen sulfide (H2S), a novel neuromodulator, is linked to the pathogenesis of several neurodegenerative disorders. Exogenous application of H2S exerts neuroprotection via anti-inflammation and anti-oxidative stress in animal and cellular models of Parkinson's disease (PD). However, the role of endogenous H2S and the contribution of its various synthases in PD remain unclear. In the present study, we found a decline of plasma and striatal sulfide level in 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mouse model...
August 1, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28769786/mild-inflammatory-profile-without-gliosis-in-the-c-rel-deficient-mouse-modeling-a-late-onset-parkinsonism
#11
Vanessa Porrini, Mariana Mota, Edoardo Parrella, Arianna Bellucci, Marina Benarese, Lara Faggi, Paolo Tonin, Pier F Spano, Marina Pizzi
The impact of neuroinflammation and microglial activation to Parkinson's disease (PD) progression is still debated. Post-mortem analysis of PD brains has shown that neuroinflammation and microgliosis are key features of end-stage disease. However, microglia neuroimaging studies and evaluation of cerebrospinal fluid (CSF) cytokines in PD patients at earlier stages do not support the occurrence of a pronounced neuroinflammatory process. PD animal models recapitulating the motor and non-motor features of the disease, and the slow and progressive neuropathology, can be of great advantage in understanding whether and how neuroinflammation associates with the onset of symptoms and neuronal loss...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28768533/progression-of-pathology-in-pink1-deficient-mouse-brain-from-splicing-via-ubiquitination-er-stress-and-mitophagy-changes-to-neuroinflammation
#12
Sylvia Torres-Odio, Jana Key, Hans-Hermann Hoepken, Júlia Canet-Pons, Lucie Valek, Bastian Roller, Michael Walter, Blas Morales-Gordo, David Meierhofer, Patrick N Harter, Michel Mittelbronn, Irmgard Tegeder, Suzana Gispert, Georg Auburger
BACKGROUND: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson's disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types. METHODS: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms...
August 2, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28736195/allelic-difference-in-mhc2ta-confers-altered-microglial-activation-and-susceptibility-to-%C3%AE-synuclein-induced-dopaminergic-neurodegeneration
#13
Itzia Jimenez-Ferrer, Michael Jewett, Ashmita Tontanahal, Marina Romero-Ramos, Maria Swanberg
Parkinson's Disease (PD) is a complex and heterogeneous neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta and pathological intracellular accumulation of alpha-synuclein (α-syn). In the vast majority of PD patients, the disease has a complex etiology, defined by multiple genetic and environmental risk factors. Common genetic variants in the human leukocyte-antigen (HLA) region have been associated to PD risk and the carriage of these can double the risk to develop PD...
July 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28730968/modulation-of-the-immune-system-for-the-treatment-of-glaucoma
#14
Katharina Bell, Nadine von Thun Und Hohenstein-Blaul, Julia Teister, Franz H Grus
At present intraocular pressure (IOP) lowering therapies are the only approach to treat glaucoma. Neuroprotective strategies to protect the retinal ganglion cells (RGC) from apoptosis are lacking to date. Results from clinical studies revealed altered immunoreactivities against retinal and optic nerve antigens in sera and aqueous humor of glaucoma patients and point toward an autoimmune involvement in glaucomatous neurodegeneration and RGC death. IgG accumulations along with plasma cells were found localised in human glaucomatous retinae in a pro-inflammatory environment possibly maintained by microglia...
July 19, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/28729832/the-role-of-microglia-in-retinal-neurodegeneration-alzheimer-s-disease-parkinson-and-glaucoma
#15
REVIEW
Ana I Ramirez, Rosa de Hoz, Elena Salobrar-Garcia, Juan J Salazar, Blanca Rojas, Daniel Ajoy, Inés López-Cuenca, Pilar Rojas, Alberto Triviño, José M Ramírez
Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28686317/synaptotagmin-11-inhibits-cytokine-secretion-and-phagocytosis-in-microglia
#16
Cuilian Du, Yalong Wang, Feifan Zhang, Shuxin Yan, Yuan Guan, Xiaoli Gong, Ting Zhang, Xiuyu Cui, Xiaomin Wang, Claire Xi Zhang
Cytokine secretion and phagocytosis are key functions of activated microglia. However, the molecular mechanisms underlying their regulation in microglia remain largely unknown. Here, we report that synaptotagmin-11 (Syt11), a non-Ca(2+) -binding Syt implicated in Parkinson disease and schizophrenia, inhibits cytokine secretion and phagocytosis in microglia. We found Syt11 expression in microglia in brain slices and primary microglia. Interestingly, Syt11-knockdown (KD) increased cytokine secretion and NO release in primary microglia both in the absence and presence of lipopolysaccharide...
July 7, 2017: Glia
https://www.readbyqxmd.com/read/28676095/toll-like-receptor-4-stimulation-with-monophosphoryl-lipid-a-ameliorates-motor-deficits-and-nigral-neurodegeneration-triggered-by-extraneuronal-%C3%AE-synucleinopathy
#17
Serena Venezia, Violetta Refolo, Alexia Polissidis, Leonidas Stefanis, Gregor K Wenning, Nadia Stefanova
BACKGROUND: Alpha-synuclein (α-syn) aggregation represents the pathological hallmark of α-synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Toll-like receptors (TLRs) are a family of highly conserved molecules that recognize pathogen-associated molecular patterns and define the innate immunity response. It was previously shown that TLR4 plays a role in the clearance of α-syn, suggesting that TLR4 up-regulation in microglia may be a natural mechanism to improve the clearance of α-syn...
July 4, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28642128/immunomodulation-of-parkinson-s-disease-using-mucuna-pruriens-mp
#18
REVIEW
Sachchida Nand Rai, Hareram Birla, Walia Zahra, Saumitra Sen Singh, Surya Pratap Singh
Immune control is associated with nigrostriatal neuroprotection for Parkinson's disease (PD); though its direct cause and effect relationships have not yet been realized and modulating the immune system for therapeutic gain has been openly discussed. While the pathobiology of PD remains in study, neuroinflammation is thought to speed nigrostriatal degeneration. The neuroinflammatory cascade associated with PD begins with aggregation of misfolded or post-translationally modified α-synuclein (α-syn). Such aggregation results in neuronal cell death and the presence of chronically activated glia (microglia and astroglia), leading to the production of proinflammatory cytokines like tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and cyclooxygenase-2 (COX-2)...
June 19, 2017: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/28540131/parkinson-s-disease-microglial-macrophage-induced-immunoexcitotoxicity-as-a-central-mechanism-of-neurodegeneration
#19
REVIEW
Russell L Blaylock
Parkinson's disease is one of the several neurodegenerative disorders that affects aging individuals, with approximately 1% of those over the age of 60 years developing the disorder in their lifetime. The disease has the characteristics of a progressive disorder in most people, with a common pattern of pathological change occurring in the nervous system that extends beyond the classical striatal degeneration of dopaminergic neurons. Earlier studies concluded that the disease was a disorder of alpha-synuclein, with the formation of aggregates of abnormal alpha-synuclein being characteristic...
2017: Surgical Neurology International
https://www.readbyqxmd.com/read/28533741/adulthood-exposure-to-lipopolysaccharide-exacerbates-the-neurotoxic-and-inflammatory-effects-of-rotenone-in-the-substantia-nigra
#20
Chun Huang, Li Zhu, Huan Li, Fu-Guo Shi, Guo-Qing Wang, Yi-Zheng Wei, Jie Liu, Feng Zhang
Parkinson's disease (PD) is the second most neurodegenerative disorder with a regional decrease of dopamine (DA) neurons in the substantia nigra (SN). Despite intense exploration, the etiology of PD progressive process remains unclear. This study was to investigate the synergistic effects of systemic inflammation of lipopolysaccharide (LPS) and neurotoxicity of rotenone (ROT) on exacerbating DA neuron lesion. Male SD adulthood rats received a single intraperitoneal injection of LPS. Seven months later, rats were subcutaneously given ROT five times a week for consecutive 4 weeks...
2017: Frontiers in Molecular Neuroscience
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