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https://www.readbyqxmd.com/read/29341898/induction-of-alpha-synuclein-pathology-in-the-enteric-nervous-system-of-the-rat-and-non-human-primate-results-in-gastrointestinal-dysmotility-and-transient-cns-pathology
#1
Fredric P Manfredsson, Kelvin C Luk, Matthew J Benskey, Aysegul Guezer, Joanna Garcia, Nathan C Kuhn, Ivette M Sandoval, Joseph R Patterson, Alana O'Mara, Reid Yonkers, Jeffrey H Kordower
Alpha-Synuclein (α-syn) is by far the most highly vetted pathogenic and therapeutic target in Parkinson's disease. Aggregated α-syn is present in sporadic Parkinson's disease, both in the central nervous system (CNS) and peripheral nervous system (PNS). The enteric division of the PNS is of particular interest because 1) gastric dysfunction is a key clinical manifestation of Parkinson's disease, and 2) Lewy pathology in myenteric and submucosal neurons of the enteric nervous system (ENS) has been referred to as stage zero in the Braak pathological staging of Parkinson's disease...
January 13, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29279394/familial-parkinson-s-point-mutation-abolishes-multiple-system-atrophy-prion-replication
#2
Amanda L Woerman, Sabeen A Kazmi, Smita Patel, Atsushi Aoyagi, Abby Oehler, Kartika Widjaja, Daniel A Mordes, Steven H Olson, Stanley B Prusiner
In the neurodegenerative disease multiple system atrophy (MSA), α-synuclein misfolds into a self-templating conformation to become a prion. To compare the biological activity of α-synuclein prions in MSA and Parkinson's disease (PD), we developed nine α-synuclein-YFP cell lines expressing point mutations responsible for inherited PD. MSA prions robustly infected wild-type, A30P, and A53T α-synuclein-YFP cells, but they were unable to replicate in cells expressing the E46K mutation. Coexpression of the A53T and E46K mutations was unable to rescue MSA prion infection in vitro, establishing that MSA α-synuclein prions are conformationally distinct from the misfolded α-synuclein in PD patients...
December 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29276384/investigation-of-the-effects-of-carbon-based-nanomaterials-on-a53t-alpha-synuclein-aggregation-using-a-whole-cell-recombinant-biosensor
#3
Soheila Mohammadi, Maryam Nikkhah, Saman Hosseinkhani
The aggregation of alpha-synuclein (αS), natively unstructured presynaptic protein, is a crucial factor leading to the pathogenesis of Parkinson's disease (PD) and other related disorders. Recent studies have shown prefibrillar and oligomeric intermediates of αS as toxic to the cells. Herein, split-luciferase complementation assay is used to design a "signal-on" biosensor to monitor oligomerization of A53T αS inside the cells. Then, the effect of carbon-based nanomaterials, such as graphene quantum dots (GQDs) and graphene oxide quantum dots (GOQDs), on A53T αS oligomerization in vitro and in living cells is investigated...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/29246724/toxic-properties-of-microsome-associated-alpha-synuclein-species-in-mouse-primary-neurons
#4
Emanuela Colla, Giulia Panattoni, Alessio Ricci, Caterina Rizzi, Lucia Rota, Nicola Carucci, Verdiana Valvano, Francesco Gobbo, Simona Capsoni, Michael K Lee, Antonino Cattaneo
α-synuclein (αS) is a small protein that self-aggregates into α-helical oligomer species and subsequently into larger insoluble amyloid fibrils that accumulate in intraneuronal inclusions during the development of Parkinson's disease. Toxicity of αS oligomers and fibrils has been long debated and more recent data are suggesting that both species can induce neurodegeneration. However while most of these data are based on differences in structure between oligomer and aggregates, often preassembled in vitro, the in vivo situation might be more complex and subcellular locations where αS species accumulate, rather than their conformation, might contribute to enhanced toxicity...
December 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29233723/the-different-faces-of-the-p-a53t-alpha-synuclein-mutation-a-screening-of-greek-patients-with-parkinsonism-and-or-dementia
#5
Marianthi Breza, Georgios Koutsis, Georgia Karadima, Constantin Potagas, Chrisoula Kartanou, Sokratis G Papageorgiou, George P Paraskevas, Elisabeth Kapaki, Leonidas Stefanis, Marios Panas
BACKGROUND: The p. A53T mutation in the alpha-synuclein (SNCA) gene is a rare cause of autosomal dominant Parkinson's disease (PD). Although generally rare, it is particularly common in the Greek population due to a founder effect. A53T-positive PD patients often develop dementia during disease course and may very rarely present with dementia. METHODS: We screened for the p. A53T SNCA mutation a total of 347 cases of Greek origin with parkinsonism and/or dementia, collected over 15 years at the Neurogenetics Unit, Eginition Hospital, University of Athens...
December 9, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29218419/an-unexpected-improvement-in-spatial-learning-and-memory-ability-in-alpha-synuclein-a53t-transgenic-mice
#6
Qi Liu, YuYu Xu, WenPing Wan, ZeGang Ma
Growing evidence suggests, as Parkinson's disease (PD) progresses, that its non-motor symptoms appear prior to or in parallel with its motor deficits. Alpha-synuclein A53T transgenic mouse (A53T) is an essential tool to investigate the onsets and the extents of PD non-motor symptoms. Our aim is to investigate spatial learning and memory ability in A53T mice. In our rotarod tests, no motor coordination impairments were detected in mice of 3, 6, 9, and 12 months old. We then investigated their spatial learning and memory ability through Morris water maze in 3- and 9-month-old mice...
December 7, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29214369/ginkgolide-k-promotes-the-clearance-of-a53t-mutation-alpha-synuclein-in-sh-sy5y-cells
#7
Wenbo Yu, Sheng Chen, Liang Cao, Jie Tang, Wei Xiao, Baoguo Xiao
Alpha-synuclein (α-syn) is associated to Parkinson's disease (PD). The aggregated form of α-syn has potential neurotoxicity. Thus, the clearance of α-syn aggregation is a plausible strategy to delay disease progression of PD. In our study, we found that the treatment of Ginkgolide B (GB) and Ginkgolide K (GK) reduced cell death, and enhanced cell proliferation in SH-SY5Y cells, which overexpressed A53T mutant α-syn. Surprisingly, GK, but not GB, promoted the clearance of A53T α-syn, which can be abolished by autophagy inhibitor 3-methyladenine, indicating that GK-induced autophagy intervened in the clearance of A53T α-syn...
December 6, 2017: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/29203207/suppression-of-autophagy-in-the-brain-of-transgenic-mice-with-overexpression-of-%C3%B0-53%C3%B0-mutant-%C3%AE-synuclein-as-an-early-event-at-synucleinopathy-progression
#8
Alexander B Pupyshev, Tatiana A Korolenko, Anna A Akopyan, Tamara G Amstislavskaya, Maria A Tikhonova
Transgenic overexpression of α-synuclein is a common model of Parkinson's disease (PD). Accumulation of А53Т-mutant α-synuclein induces three autophagy cell response: the inhibition of autophagy caused by the accumulation of α-synuclein, compensatory activation of macroautophagy in response to inhibition of the CMA, and toxic effects of mutant α-synuclein accompanied by the activation of autophagy. The overall effect of long-term overexpression of mutant α-synuclein in vivo remained unclear. Here we evaluated the activity of autophagy in the frontal cortex, striatum and s...
December 1, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29200905/mptp-induced-vulnerability-of-dopamine-neurons-in-a53t-%C3%AE-synuclein-overexpressed-mice-with-the-potential-involvement-of-dj-1-downregulation
#9
Seongmi Lee, Seung Tack Oh, Ha Jin Jeong, Sok Cheon Pak, Hi-Joon Park, Jongpil Kim, Hyun-Seok Cho, Songhee Jeon
Familial Parkinson's disease (PD) has been linked to point mutations and duplication of the α-synuclein (α-syn) gene. Mutant α-syn expression increases the vulnerability of neurons to exogenous insults. In this study, we developed a new PD model in the transgenic mice expressing mutant hemizygous (hemi) or homozygous (homo) A53T α-synuclein (α-syn Tg) and their wildtype (WT) littermates by treatment with sub-toxic (10 mg/kg, i.p., daily for 5 days) or toxic (30 mg/kg, i.p., daily for 5 days) dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)...
November 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/29191831/structural-features-of-%C3%AE-synuclein-amyloid-fibrils-revealed-by-raman-spectroscopy
#10
Jessica D Flynn, Ryan P McGlinchey, Robert L Walker, Jennifer C Lee
Parkinson's disease (PD) is associated with the formation of α-synuclein amyloid fibrils. Elucidating the role of these β-sheet-rich fibrils in disease progression is crucial; however, collecting detailed structural information on amyloids is inherently difficult due to their insoluble, non-crystalline, and polymorphic nature. Here, we show that Raman spectroscopy is a facile technique for characterizing structural features of α-synuclein fibrils. Combining Raman spectroscopy with aggregation kinetics and transmission electron microscopy (TEM), we examined the effects of pH and ionic strength as well as four PD-related mutations (A30P, E46K, G51D, and A53T) on α-synuclein fibrils...
November 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29183796/heat-shock-protein-70-suppresses-neuroinflammation-induced-by-%C3%AE-synuclein-in-astrocytes
#11
Wen-Wen Yu, Sheng-Nan Cao, Cai-Xia Zang, Lu Wang, Han-Yu Yang, Xiu-Qi Bao, Dan Zhang
Neuroinflammation triggered by activation of glial cells plays an important role in the pathophysiology of several neurodegenerative diseases including Parkinson's disease (PD). Besides microglia, astrocytes are also critical in initiating and perpetuating inflammatory process associated with PD. Heat shock protein 70 (Hsp70) is originally described as intracellular chaperone, however, recent study revealed that it had anti-inflammatory effects as well. The present study is designed to investigate whether Hsp70 mediates neuroinflammation in astrocytes...
November 25, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29173981/glucocerebrosidase-haploinsufficiency-in-a53t-%C3%AE-synuclein-mice-impacts-disease-onset-and-course
#12
Nahid Tayebi, Loukia Parisiadou, Bahafta Berhe, Ashley N Gonzalez, Jenny Serra-Vinardell, Raphael J Tamargo, Emerson Maniwang, Zachary Sorrentino, Hideji Fujiwara, Richard J Grey, Shahzeb Hassan, Yotam N Blech-Hermoni, Chuyu Chen, Ryan McGlinchey, Chrissy Makariou-Pikis, Mieu Brooks, Edward I Ginns, Daniel S Ory, Benoit I Giasson, Ellen Sidransky
Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCAA53T) transgene were crossed with heterozygous null gba mice (gba+/-). Survival analysis of 84 mice showed that in gba+/-//SNCAA53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba+/+//SNCAA53T mice (p-values 0...
November 21, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29158022/activation-of-the-nrf2-signaling-pathway-and-neuroprotection-of-nigral-dopaminergic-neurons-by-a-novel-synthetic-compound-kms99220
#13
Ji Ae Lee, Hyo Jin Son, Ji Won Choi, Jinwoo Kim, Se Hee Han, Nari Shin, Ji Hyun Kim, Soo Jeong Kim, Jun Young Heo, Dong Jin Kim, Ki Duk Park, Onyou Hwang
The transcription factor Nrf2 is known to induce gene expression of antioxidant enzymes and proteasome subunits. Because both oxidative stress and protein aggregation have damaging effects on neurons, activation of the Nrf2 signaling should be beneficial against neurodegeneration. In this study, we report a novel synthetic morpholine-containing chalcone KMS99220 that confers neuroprotection. It showed high binding affinity to the Nrf2 inhibitory protein Keap-1 and increased nuclear translocation of Nrf2 and gene expression of the antioxidant enzymes heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1, and the catalytic and modifier subunits of glutamate-cysteine ligase in dopaminergic CATH...
November 17, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/29150334/a-routinely-used-protein-staining-dye-acts-as-an-inhibitor-of-wild-type-and-mutant-alpha-synuclein-aggregation-and-modulator-of-neurotoxicity
#14
Nuzhat Ahsan, Ibrar Ahmed Siddique, Sarika Gupta, Avadhesha Surolia
Inhibition of amyloid formation along with modulation of toxicity employing small molecules is emerging as a potential therapeutic approach for protein misfolding disorders which includes Parkinson's disease, Alzheimer's disease and Multiple System Atrophy etc. Countless current interventional strategies for treating α-synucleinopathies consider using peptidic and non-peptidic inhibitors for arresting fibrillisation, disrupting existing fibrils and reducing associated toxicity. One group of molecules less exploited in this regard are triphenylmethane dyes...
October 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29130486/rtp801-is-a-critical-factor-in-the-neurodegeneration-process-of-a53t-alpha-synuclein-in-a-mouse-model-of-parkinson-s-disease-under-chronic-restraint-stress
#15
Zhao Zhang, Shi-Feng Chu, Sha-Sha Wang, Yi-Na Jiang, Yan Gao, Peng-Fei Yang, Qi-Di Ai, Nai-Hong Chen
BACKGROUND AND PURPOSE: The incidence of Parkinson's disease exhibited a younger tendency in recent years with the constantly increased stressors of modern society, but this relationship remains obscured. We performed this study to investigate whether stress contributes to this tendency and identify the executor during this process. EXPERIMENTAL APPROACH: Ten-month-old α-synuclein A53T mice, a PD mice model, were treated with chronic restraint stress (CRS) to simulate a PD-sensitive person with constant stress stimulation...
November 11, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29129675/alpha-synuclein-dimerization-in-erythrocytes-of-patients-with-genetic-and-non-genetic-forms-of-parkinson-s-disease
#16
Nikolaos Papagiannakis, Christos Koros, Maria Stamelou, Athina-Maria Simitsi, Matina Maniati, Roubina Antonelou, Dimitra Papadimitriou, Georgia Dermentzaki, Marina Moraitou, Helen Michelakakis, Leonidas Stefanis
BACKGROUND: Variations of α-synuclein levels or species have been reported in Parkinson's Disease (PD). There has been little systematic examination of erythrocytes, a rich source of α-synuclein. METHODS: Erythrocyte membranes were obtained from PD patients (mutation carriers in the α-synuclein gene (A53T-PD) and glucocerebrosidase gene (GBA-PD) (n=18 each), and patients without known mutations (GU-PD, n=56)), and age-/sex-matched controls (n=56). Levels of monomeric and dimeric α-synuclein were assessed using Western immunoblotting...
November 9, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29040593/oral-exposure-to-paraquat-triggers-earlier-expression-of-phosphorylated-%C3%AE-synuclein-in-the-enteric-nervous-system-of-a53t-mutant-human-%C3%AE-synuclein-transgenic-mice
#17
Nicolas Naudet, Emilie Antier, Damien Gaillard, Eric Morignat, Latifa Lakhdar, Thierry Baron, Anna Bencsik
The misfolded α-synuclein protein, phosphorylated at serine 129 (pSer129 α-syn), is the hallmark of Parkinson disease (PD). Detected also in the enteric nervous system (ENS), it supports the recent theory that PD could start in the gut, rather than the brain. In a previous study, using a transgenic mouse model of human synucleinopathies expressing the A53T mutant α-synuclein (TgM83), in which a neurodegenerative process associated with α-synuclein occurs spontaneously in the brain, we have shown earlier onset of pSer129 α-syn in the ENS...
December 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29017011/altered-volatile-organic-compound-profile-in-transgenic-rats-bearing-a53t-mutation-of-human-%C3%AE-synuclein-comparison-with-dopaminergic-and-serotonergic-denervation
#18
John P M Finberg, Yuval Aluf, Yelena Loboda, Morad K Nakhleh, Raneen Jeries, Manal Abud-Hawa, Salman Zubedat, Avi Avital, Soliman Khatib, Jacob Vaya, Hossam Haick
Early diagnosis of Parkinson's disease (PD) is of great importance due its progressive phenotype. Neuroprotective drugs could potentially slow down disease progression if used at early stages. Previously, we have reported an altered content of volatile organic compounds (VOCs) in the breath of rats following a 50% reduction in striatal dopamine (DA) content induced by 6-hydroxydopamine. We now report on the difference in the breath-print and content of VOCs between rats with mild and severe lesions of DA neurons, serotonergic neuronal lesions, and transgenic (Tg) rats carrying the PD-producing A53T mutation of the SNCA (α-synuclein) gene...
October 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28990084/neuroprotective-effect-of-chondroitin-sulfate-on-sh%C3%A2-sy5y-cells-overexpressing-wild%C3%A2-type-or-a53t-mutant-%C3%AE-%C3%A2-synuclein
#19
Chuanxia Ju, Jianjun Gao, Lin Hou, Lei Wang, Fang Zhang, Fusheng Sun, Tingting Zhang, Pingping Xu, Zhenyan Shi, Fang Hu, Congxiao Zhang
Accumulation of α‑synuclein (α‑SYN) is a common pathology for Parkinson's disease (PD). There is abundant evidence that the toxic‑gain‑of‑function of α‑SYN's is associated with aggregation and consequent effects. To assess the potential of chondroitin sulfate (CS) in this regard, the present study investigated its neuroprotective on SH‑SY5Y cells overexpressing wild‑type (WT) or A53T mutant α‑SYN. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential were detected by flow cytometry...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28964772/prion-like-transmission-of-%C3%AE-synuclein-pathology-in-the-context-of-an-nfl-null-background
#20
Nicola J Rutherford, Mieu Brooks, Cara J Riffe, Kimberly-Marie M Gorion, Jasie K Howard, Jess-Karan S Dhillon, Benoit I Giasson
Neurofilaments are a major component of the axonal cytoskeleton in neurons and have been implicated in a number of neurodegenerative diseases due to their presence within characteristic pathological inclusions. Their contributions to these diseases are not yet fully understood, but previous studies investigated the effects of ablating the obligate subunit of neurofilaments, low molecular mass neurofilament subunit (NFL), on disease phenotypes in transgenic mouse models of Alzheimer's disease and tauopathy. Here, we tested the effects of ablating NFL in α-synuclein M83 transgenic mice expressing the human pathogenic A53T mutation, by breeding them onto an NFL null background...
November 20, 2017: Neuroscience Letters
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