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https://www.readbyqxmd.com/read/29771508/comparison-of-kinetics-toxicity-oligomers-formation-and-membrane-binding-capacity-of-%C3%AE-synuclein-familial-mutations-at-a53-site-including-newly-discovered-a53v-mutation
#1
Ganesh M Mohite, Rakesh Kumar, Rajlaxmi Panigrahi, Ambuja Navalkar, Nitu Singh, Debalina Datta, Surabhi Mehra, Soumik Ray, Laxmikant G Gadhe, Subhadeep Das, Namrata Singh, Debdeep Chatterjee, Ashutosh Kumar, Samir K Maji
The involvement of α-synuclein (α-Syn) amyloid formation in Parkinson's disease (PD) pathogenesis is supported by the discovery of α-Syn gene (SNCA) mutations linked with familial PD, which are known to modulate the oligomerization and aggregation of α-Syn. Recently, the A53V mutation has been discovered, which leads to the late-onset PD. In the present study, we characterized for the first time the biophysical properties including the aggregation propensities, toxicity of aggregated species and membrane binding capability of A53V along with all familial mutations at A53 position...
May 17, 2018: Biochemistry
https://www.readbyqxmd.com/read/29770111/chronic-caffeine-treatment-protects-against-%C3%AE-synucleinopathy-by-reestablishing-autophagy-activity-in-the-mouse-striatum
#2
Yanan Luan, Xiangpeng Ren, Wu Zheng, Zhenhai Zeng, Yingzi Guo, Zhidong Hou, Wei Guo, Xingjun Chen, Fei Li, Jiang-Fan Chen
Despite converging epidemiological evidence for the inverse relationship of regular caffeine consumption and risk of developing Parkinson's disease (PD) with animal studies demonstrating protective effect of caffeine in various neurotoxin models of PD, whether caffeine can protect against mutant α-synuclein (α-Syn) A53T-induced neurotoxicity in intact animals has not been examined. Here, we determined the effect of chronic caffeine treatment using the α-Syn fibril model of PD by intra-striatal injection of preformed A53T α-Syn fibrils...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29749529/%C3%AE-%C3%A2-synuclein-induces-apoptosis-of-astrocytes-by-causing-dysfunction-of-the-endoplasmic-reticulum%C3%A2-golgi-compartment
#3
Mei Liu, Lixia Qin, Lili Wang, Jieqiong Tan, Hainan Zhang, Jianguang Tang, Xiangmin Shen, Liming Tan, Chunyu Wang
Although previous work has demonstrated that the overexpression of wild‑type or mutant α‑synuclein (α‑syn) can induce cell death via a number of different mechanisms, including oxidative stress, dysfunction of the ubiquitin‑proteasome degradation system, mitochondrial damage and endoplasmic reticulum (ER) stress, research interest has primarily focused on neurons. However, there is accumulating evidence that suggests that astrocytes may be involved in the earliest changes, as well as the progression of Parkinson's disease (PD), though the role of α‑syn in astrocytes has not been widely studied...
May 9, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29747690/a53t-%C3%AE-synuclein-overexpression-in-murine-locus-coeruleus-induces-parkinson-s-disease-like-pathology-in-neurons-and-glia
#4
Martin Timo Henrich, Fanni Fruzsina Geibl, Bolam Lee, Wei-Hua Chiu, James Benjamin Koprich, Jonathan Michael Brotchie, Lars Timmermann, Niels Decher, Lina Anita Matschke, Wolfgang Hermann Oertel
Degeneration of noradrenergic locus coeruleus neurons occurs during the prodromal phase of Parkinson's disease and contributes to a variety of non-motor symptoms, e.g. depression, anxiety and REM sleep behavior disorder. This study was designed to establish the first locus coeruleus α-synucleinopathy mouse model, which should provide sufficient information about the time-course of noradrenergic neurodegeneration, replicate cardinal histopathological features of the human Parkinson's disease neuropathology and finally lead to robust histological markers, which are sufficient to assess the pathological changes in a quantitative and qualitative way...
May 10, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29747217/fyco1-mediates-clearance-of-%C3%AE-synuclein-aggregates-through-a-rab7-dependent-mechanism
#5
Theodora Saridaki, Markus Nippold, Elisabeth Dinter, Andreas Roos, Leonie Diederichs, Luisa Fensky, Jörg B Schulz, Björn H Falkenburger
Parkinson disease can be caused by mutations in the α-synuclein gene and is characterized by aggregates of α-synuclein protein. We have previously shown that overexpression of the small GTPase Rab7 can induce clearance of α-synuclein aggregates. In this study, we investigate which Rab7 effectors mediate this effect. To model Parkinson disease we expressed the pathogenic A53T mutant of α-synuclein in HEK293T cells and Drosophila melanogaster. We tested the Rab7 effectors FYVE and coiled-coil domain-containing protein 1 (FYCO1) and Rab-interacting lysosomal protein (RILP)...
May 10, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29713567/palmitic-acid-induces-neurotoxicity-and-gliatoxicity-in-sh-sy5y-human-neuroblastoma-and-t98g-human-glioblastoma-cells
#6
Yee-Wen Ng, Yee-How Say
Background: Obesity-related central nervous system (CNS) pathologies like neuroinflammation and reactive gliosis are associated with high-fat diet (HFD) related elevation of saturated fatty acids like palmitic acid (PA) in neurons and astrocytes of the brain. Methods: Human neuroblastoma cells SH-SY5Y (as a neuronal model) and human glioblastoma cells T98G (as an astrocytic model), were treated with 100-500 µM PA, oleic acid (OA) or lauric acid (LA) for 24 h or 48 h, and their cell viability was assessed by 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay...
2018: PeerJ
https://www.readbyqxmd.com/read/29707965/an-enriched-environment-ameliorates-oxidative-stress-and-olfactory-dysfunction-in-parkinson-s-disease-with-%C3%AE-synucleinopathy
#7
Soohyun Wi, Jang Woo Lee, MinGi Kim, Chang-Hwan Park, Sung-Rae Cho
Parkinson's disease (PD) features nonmotor symptoms such as olfactory dysfunction referred to as hyposmia, an initial sign of disease progression. Metabolic dysfunction can contribute to neurodegenerative diseases, and various xenobiotics and endogenous compounds are also involved in the pathogenesis of PD. Although aerobic exercise was found to induce preservation or improvement in olfactory function in PD patients in a recent study, the exact underlying mechanism for this effect is not clear. We aimed to investigate the influence of an enriched environment (EE) on olfactory dysfunction especially via metabolic pathways related to detoxification enzymes...
January 1, 2018: Cell Transplantation
https://www.readbyqxmd.com/read/29703245/d409h-gba1-mutation-accelerates-the-progression-of-pathology-in-a53t-%C3%AE-synuclein-transgenic-mouse-model
#8
Donghoon Kim, Heehong Hwang, Seulah Choi, Sang Ho Kwon, Suhyun Lee, Jae Hong Park, SangMin Kim, Han Seok Ko
Heterozygous mutations in glucocerebrosidase 1 (GBA1) are a major genetic risk factor for Parkinson's disease and Dementia with Lewy bodies. Mutations in GBA1 leads to GBA1 enzyme deficiency, and GBA1-associated parkinsonism has an earlier age of onset and more progressive parkinsonism. To investigate a potential influence of GBA1 deficiency caused by mutations in GBA1 on the disease progression of PD, GBA1 mice carrying D409H knock-in mutation were crossbred with the human A53T (hA53T) α-synuclein transgenic mice...
April 27, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29688812/nitration-of-microtubules-blocks-axonal-mitochondrial-transport-in-a-human-pluripotent-stem-cell-model-of-parkinson-s-disease
#9
Morgan G Stykel, Kayla Humphries, Mathew P Kirby, Chris Czaniecki, Tinya Wang, Tammy Ryan, Vladimir Bamm, Scott D Ryan
Neuronal loss in Parkinson's disease (PD) is associated with aberrant mitochondrial function in dopaminergic (DA) neurons of the substantia nigra pars compacta. An association has been reported between PD onset and exposure to mitochondrial toxins, including the agrochemicals paraquat (PQ), maneb (MB), and rotenone (Rot). Here, with the use of a patient-derived stem cell model of PD, allowing comparison of DA neurons harboring a mutation in the α-synuclein (α-syn) gene ( SNCA-A53T) against isogenic, mutation-corrected controls, we describe a novel mechanism whereby NO, generated from SNCA-A53T mutant neurons exposed to Rot or PQ/MB, inhibits anterograde mitochondrial transport through nitration of α-tubulin (α-Tub)...
April 24, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29681846/high-dietary-iron-supplement-induces-the-nigrostriatal-dopaminergic-neurons-lesion-in-transgenic-mice-expressing-mutant-a53t-human-alpha-synuclein
#10
Fengju Jia, Ning Song, Weiwei Wang, Xixun Du, Yajing Chi, Hong Jiang
Both alpha-synuclein aggregation and iron deposits are neuropathological hallmarks of Parkinson's disease (PD). We are particularly interested in whether iron could synergize with alpha-synuclein pathology in vivo , especially in the nigrostriatal system. In the present study, we reported transgenic mice with overexpressing human A53T alpha-synuclein, as well as WT mice with high dietary iron displayed hyperactive motor coordination and impaired colonic motility, compared with those with basal dietary iron...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29649746/degradation-of-alpha-synuclein-by-dendritic-cell-factor-1-delays-neurodegeneration-and-extends-lifespan-in-drosophila
#11
Shiqing Zhang, Ruili Feng, Yanhui Li, Linhua Gan, Fangfang Zhou, Shiquan Meng, Qian Li, Tieqiao Wen
Parkinson's disease (PD) is a common neurodegenerative disease associated with the progressive loss of dopaminergic neurons in the substantia nigra. Proteinaceous depositions of alpha-synuclein (α-syn) and its mutations, A30P and A53T, are one important characteristic of PD. However, little is known about their aggregation and degradation mechanisms. Dendritic cell factor 1 (DCF1) is a membrane protein that plays important roles in nerve development in mouse. In this study, we aimed to show that DCF1 overexpression in a PD Drosophila model significantly ameliorates impaired locomotor behavior in third instar larvae and normalizes neuromuscular junction growth...
March 13, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29624735/cx3cr1-deficiency-exacerbates-alpha-synuclein-a53t-induced-neuroinflammation-and-neurodegeneration-in-a-mouse-model-of-parkinson-s-disease
#12
Sara Castro-Sánchez, Ángel J García-Yagüe, Tresa López-Royo, Maria Casarejos, José Luis Lanciego, Isabel Lastres-Becker
Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons of the substantia nigra and the accumulation of protein aggregates, called Lewy bodies, where the most abundant is alpha-synuclein (α-SYN). Mutations of the gene that codes for α-SYN (SNCA), such as the A53T mutation, and duplications of the gene generate cases of PD with autosomal dominant inheritance. As a result of the association of inflammation with the neurodegeneration of PD, we analyzed whether overexpression of wild-type α-SYN (α-SYNWT ) or mutated α-SYN (α-SYNA53T ) are involved in the neuronal dopaminergic loss and inflammation process, along with the role of the chemokine fractalkine (CX3CL1) and its receptor (CX3CR1)...
April 6, 2018: Glia
https://www.readbyqxmd.com/read/29559809/the-convergence-of-dopamine-and-%C3%AE-synuclein-implications-for-parkinson-s-disease
#13
Danielle E Mor, Harry Ischiropoulos
In Parkinson's disease (PD), the loss of dopamine-producing neurons in the substantia nigra (SN) leads to severe motor impairment, and pathological inclusions known as Lewy bodies contain aggregated α-synuclein protein. The relationship of α-synuclein aggregation and dopaminergic degeneration is unclear. This commentary highlights a recent study showing that the interaction of α-synuclein with dopamine may be an important mechanism underlying disease. Elevating dopamine levels in mice expressing human α-synuclein with the A53T familial PD mutation recapitulated key features of PD, including progressive neurodegeneration of the SN and decreased ambulation...
2018: Journal of Experimental Neuroscience
https://www.readbyqxmd.com/read/29551576/hmgb1-promotes-the-starvation-induced-autophagic-degradation-of-%C3%AE-synuclein-in-sh-sy5y-cells-atg-5-dependently
#14
Yi Guan, Yiping Li, Gang Zhao, Yunqian Li
Impaired autophagic clearance of aggregated α-synuclein is considered as one of key mechanisms underlining Parkinson disease (PD). High-mobility group protein B1 (HMGB1) has recently been demonstrated to mediate persistent neuroinflammation and consequent progressive neurodegeneration by promoting multiple inflammatory and neurotoxic factors. In this study, we examined the influence of the overexpression of wild-type (WT) and mutant-type (MT, A53T and A30P) α-synuclein on the autophagy in neuroblastoma SH-SY5Y cells under starvation, and then investigated the regulation of endogenous HMGB1 on the α-synuclein degradation and on the starvation-induced autophagy in the α-synuclein-overexpressed SH-SY5Y cells...
March 15, 2018: Life Sciences
https://www.readbyqxmd.com/read/29547959/modulation-of-%C3%AE-glucocerebrosidase-increases-%C3%AE-synuclein-secretion-and-exosome-release-in-mouse-models-of-parkinson-s-disease
#15
Vassilis E Papadopoulos, Georgia Nikolopoulou, Ivi Antoniadou, Antonia Karachaliou, Giovanna Arianoglou, Evangelia Emmanouilidou, S Pablo Sardi, Leonidas Stefanis, Kostas Vekrellis
Glucocerebrosidase gene (GBA) mutations are the most common genetic contributor to Parkinson's Disease (PD) and are associated with decreased Glucocerebrosidase (GCase) enzymatic activity in PD. PD patients without GBA mutations also exhibit lower levels of GCase activity in the central nervous system (CNS) suggesting a potential contribution of the enzyme activity in disease pathogenesis, possibly by alteration of lysosomal function. α-synuclein, a protein with a central role in PD pathogenesis, has been shown to be secreted partly in association with exosomes...
March 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29544548/tau-oligomers-mediate-%C3%AE-synuclein-toxicity-and-can-be-targeted-by-immunotherapy
#16
Julia E Gerson, Kathleen M Farmer, Natalie Henson, Diana L Castillo-Carranza, Mariana Carretero Murillo, Urmi Sengupta, Alan Barrett, Rakez Kayed
BACKGROUND: We have evaluated the efficacy of targeting the toxic, oligomeric form of tau protein by passive immunotherapy in a mouse model of synucleinopathy. Parkinson's disease and Lewy body dementia are two of the most common neurodegenerative disorders and are primarily characterized by the accumulation of α-synuclein in Lewy bodies. However, evidence shows that smaller, oligomeric aggregates are likely the most toxic form of the protein. Moreover, a large body of research suggests that α-synuclein interacts with tau in disease and may act in a synergistic mechanism, implicating tau oligomers as a potential therapeutic target...
March 15, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29506601/effects-of-ginkgo-biloba-extract-on-a53t-%C3%AE-synuclein-transgenic-mouse-models-of-parkinson-s-disease
#17
Shaosong Kuang, Lin Yang, Ziliang Rao, Zhiyong Zhong, Jinfeng Li, Haichao Zhong, Lulu Dai, Xiaojiang Tang
BACKGROUND: Parkinson's disease (PD) is a degenerative disorder of the central nervous system mainly affecting the motor system. Presently, there is no effective and safe drug to treat patients with PD. Ginkgo biloba extract (GBE), obtained from leaves of the Ginkgo biloba tree, is a complex mixture of ingredients primarily containing two active components: flavonoids and terpenoids. In this study, we investigated the effects of GBE on A53T α-synuclein transgenic mice, a PD model that has better simulated the progression of PD patients than other models such as the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced PD model...
March 2018: Canadian Journal of Neurological Sciences. le Journal Canadien des Sciences Neurologiques
https://www.readbyqxmd.com/read/29503608/silencing-of-glucocerebrosidase-gene-in-drosophila-enhances-the-aggregation-of-parkinson-s-disease-associated-%C3%AE-synuclein-mutant-a53t-and-affects-locomotor-activity
#18
Salema B Abul Khair, Nisha R Dhanushkodi, Mustafa T Ardah, Wenfeng Chen, Yufeng Yang, M Emdadul Haque
Background: Mutations in glucocerebrosidase (GBA), a lysosomal enzyme are the most common genetic risk factor for developing Parkinson's disease (PD). We studied how reduced GCase activity affects α-synuclein (α-syn) and its mutants (A30P and A53T) aggregation, neurodegeneration, sleep and locomotor behavior in a fly model of PD. Methods: We developed drosophila with GBA gene knockdown (RNAi) (with reduced GCase activity) that simultaneously expresses either wildtype (WT) or mutants such as A30P or A53T α-syn...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29458128/aggregation-prone-regions-in-hypk-help-it-to-form-sequestration-complex-for-toxic-protein-aggregates
#19
Debasish Kumar Ghosh, Ajit Roy, Akash Ranjan
Protein aggregates result from altered structural conformations and they can perturb cellular homeostasis. Prevention mechanisms, which function against protein aggregation by modulatory processes, are diverse and redundant. In this study, we have characterized Huntingtin interacting protein K (HYPK) as a global aggregation-regulatory protein. We report the mechanistic details of how HYPK's aggregation-prone regions allow it to sense and prevent other toxic protein's aggregation by forming unique annular-shaped sequestration complexes...
March 30, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29438043/selective-cognitive-impairment-and-hyposmia-in-p-a53t-snca-pd-vs-typical-pd
#20
Christos Koros, Maria Stamelou, Athina Simitsi, Ion Beratis, Dimitra Papadimitriou, Nikolaos Papagiannakis, Stella Fragkiadaki, Dionysia Kontaxopoulou, Sokratis G Papageorgiou, Leonidas Stefanis
OBJECTIVE: To evaluate nonmotor symptoms in early SNCA /p.A53T Parkinson disease (PD) (A53T PD) compared to typical PD (tPD). METHODS: The presence of hyposmia, neuropsychiatric, dysautonomic, and sleep disturbances was assessed by standardized questionnaires and validated scales in 18 patients with A53T PD and 18 patients with tPD, matched for age, sex, and disease duration. All patients were enrolled into the Parkinson's Progression Markers Initiative study. RESULTS: The levodopa equivalent daily dose was higher in the A53T PD ( p = 0...
March 6, 2018: Neurology
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