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https://www.readbyqxmd.com/read/28520872/glucocerebrosidase-deficiency-in-dopaminergic-neurons-induces-microglial-activation-without-neurodegeneration
#1
Federico N Soria, Michel Engeln, Marta Martinez-Vicente, Christelle Glangetas, María José López-González, Sandra Dovero, Benjamin Dehay, Elisabeth Normand, Miquel Vila, Alexandre Favereaux, François Georges, Christophe Lo Bianco, Erwan Bezard, Pierre-Olivier Fernagut
Mutations in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase (GBA1) are important risk factors for Parkinson's disease (PD). In vitro, altered GBA1 activity promotes alpha-synuclein accumulation while elevated levels of alpha-synuclein compromise GBA1 function, thus supporting a pathogenic mechanism in PD. However, the mechanisms by which GBA1 deficiency is linked to increased risk of PD remains elusive, partially because of lack of aged models of GBA1 deficiency. Since knocking-out GBA1 in the entire brain induces massive neurodegeneration and early death, we generated a mouse model of GBA1 deficiency amenable to investigate the long-term consequences of compromised GBA1 function in dopaminergic neurons...
May 17, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28482862/higher-levels-of-myelin-phospholipids-in-brains-of-neuronal-%C3%AE-synuclein-transgenic-mice-precede-myelin-loss
#2
Jessica Grigoletto, Katharina Pukaß, Ayelet Gamliel, Dana Davidi, Rachel Katz-Brull, Christiane Richter-Landsberg, Ronit Sharon
α-Synuclein is a protein involved in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We investigated the role of neuronal α-Syn in myelin composition and abnormalities. The phospholipid content of purified myelin was determined by (31)P NMR in two mouse lines modeling PD, PrP-A53T α-Syn and Thy-1 wt-α-Syn. Significantly higher levels of phospholipids were detected in myelin purified from brains of these α-Syn transgenic mouse models than in control mice...
May 8, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28476570/expression-signatures-of-long-non-coding-rna-in-the-substantia-nigra-of-pre-symptomatic-mouse-model-of-parkinson-s-disease
#3
Fengjuan Jiao, Qingzhi Wang, Pei Zhang, Lulu Bu, Jianguo Yan, Bo Tian
Parkinson's disease (PD) is an age-dependent neurodegenerative disease that can be caused by a variety of factors. Growing evidence shows that prior to the motor phase of PD can express molecular or imaging markers. Many long non-coding RNAs (lncRNAs) have been identified in neurodegenerative disease. However, the biogenesis and function of lncRNAs in the pre-symptomatic stage of PD is poorly understood. Here, we profiled the expression of lncRNAs and mRNAs in the substantia nigra pars compacta (SNpc) of pre-symptomatic mice over-expressing human A30P*A53T α-synuclein by microarray analysis...
May 2, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28470693/stn-dbs-is-neuroprotective-in-the-a53t-%C3%AE-synuclein-parkinson-s-disease-rat-model
#4
Thomas Musacchio, Maike Rebenstorff, Felix Fluri, Jonathan M Brotchie, Jens Volkmann, James B Koprich, Chi Wang Ip
OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective symptomatic therapy for motor deficits in Parkinson's disease (PD). An additional, disease-modifying effect has been suspected from studies in toxin-based PD animal models, but these models do not reflect the molecular pathology and progressive nature of PD, that would be required to evaluate a disease-modifying action. Defining a disease-modifying effect, could radically change the way in which DBS is used in PD...
May 3, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28448035/bioluminescence-imaging-of-neuroinflammation-in-transgenic-mice-after-peripheral-inoculation-of-alpha-synuclein-fibrils
#5
Sara Breid, Maria E Bernis, Julius B Tachu, Maria C Garza, Holger Wille, Gültekin Tamgüney
To study the prion-like behavior of misfolded alpha-synuclein, mouse models are needed that allow fast and simple transmission of alpha-synuclein prionoids, which cause neuropathology within the central nervous system (CNS). Here we describe that intraglossal or intraperitoneal injection of alpha-synuclein fibrils into bigenic Tg(M83(+/-):Gfap-luc(+/-)) mice, which overexpress human alpha-synuclein with the A53T mutation from the prion protein promoter and firefly luciferase from the promoter for glial fibrillary acidic protein (Gfap), is sufficient to induce neuropathologic disease...
April 13, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28442946/optogenetic-rescue-of-locomotor-dysfunction-and-dopaminergic-degeneration-caused-by-alpha-synuclein-and-eko-genes
#6
Cheng Qi, Scott Varga, Soo-Jin Oh, C Justin Lee, Daewoo Lee
α-Synuclein (α-Syn) is a small presynaptic protein and its mutant forms (e.g. A53T) are known to be directly associated with Parkinson's disease (PD). Pathophysiological mechanisms underlying α-Syn-mediated neurodegeneration in PD still remain to be explored. However, several studies strongly support that overexpression of mutant α-Syn causes reduced release of dopamine (DA) in the brain, and contributes to motor deficits in PD. Using a favorable genetic model Drosophila larva, we examined whether reduced DA release is enough to induce key PD symptoms (i...
April 2017: Experimental Neurobiology
https://www.readbyqxmd.com/read/28416701/defective-synaptic-connectivity-and-axonal-neuropathology-in-a-human-ipsc-based-model-of-familial-parkinson-s-disease
#7
Georgia Kouroupi, Era Taoufik, Ioannis S Vlachos, Konstantinos Tsioras, Nasia Antoniou, Florentia Papastefanaki, Dafni Chroni-Tzartou, Wolfgang Wrasidlo, Delphine Bohl, Dimitris Stellas, Panagiotis K Politis, Kostas Vekrellis, Dimitra Papadimitriou, Leonidas Stefanis, Piotr Bregestovski, Artemis G Hatzigeorgiou, Eliezer Masliah, Rebecca Matsas
α-Synuclein (αSyn) is the major gene linked to sporadic Parkinson's disease (PD), whereas the G209A (p.A53T) αSyn mutation causes a familial form of PD characterized by early onset and a generally severe phenotype, including nonmotor manifestations. Here we generated de novo induced pluripotent stem cells (iPSCs) from patients harboring the p.A53T mutation and developed a robust model that captures PD pathogenic processes under basal conditions. iPSC-derived mutant neurons displayed novel disease-relevant phenotypes, including protein aggregation, compromised neuritic outgrowth, and contorted or fragmented axons with swollen varicosities containing αSyn and Tau...
May 2, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28413000/derivation-of-mouse-embryonic-stem-cell-lines-from-tyrosine-hydroxylase-reporter-mice-crossed-with-a-human-snca-transgenic-mouse-model-of-parkinson-s-disease
#8
Margarita Chumarina, Carla Azevedo, Julie Bigarreau, Clémentine Vignon, Kwang-Soo Kim, Jia-Yi Li, Laurent Roybon
Mouse embryonic stem cell (mESC) lines were derived by crossing heterozygous transgenic (tg) mice expressing green fluorescent protein (GFP) under the control of the rat tyrosine hydroxylase (TH) promoter, with homozygous alpha-synuclein (aSYN) mice expressing human mutant SNCA(A53T) under the control of the mouse Prion promoter (MoPrP), or wildtype (WT) mice. The expression of GFP and human aSYN was validated by immunocytochemistry in midbrain neuron cultures upon differentiation of mESC lines using stromal cell-derived inducing activity...
March 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28373279/a-sensitive-assay-reveals-structural-requirements-for-alpha-synuclein-fibril-growth
#9
Dhruva D Dhavale, Christina Tsai, Devika P Bagchi, Laura A Engel, Jonathan Sarezky, Paul T Kotzbauer
The accumulation of alpha-synuclein (α-syn) fibrils in neuronal inclusions is the defining pathological process in Parkinson disease (PD). A pathogenic role for α-syn fibril accumulation is supported by the identification of dominantly inherited α-syn (SNCA) gene mutations in rare cases of familial PD. Fibril formation involves a spontaneous nucleation event in which soluble α-syn monomers associate to form seeds, followed by fibril growth during which monomeric α-syn molecules sequentially associate with existing seeds...
April 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28360124/genetic-mutations-linked-to-parkinson-s-disease-differentially-control-nucleolar-activity-in-pre-symptomatic-mouse-models
#10
Valentin Evsyukov, Andrii Domanskyi, Holger Bierhoff, Suzana Gispert, Rasem Mustafa, Falk Schlaudraff, Birgit Liss, Rosanna Parlato
Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting that nucleolar dysfunction could be a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human α-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1...
May 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28300069/extracellular-%C3%AE-synuclein-induces-sphingosine-1-phosphate-receptor-subtype-1-uncoupled-from-inhibitory-g-protein-leaving-%C3%AE-arrestin-signal-intact
#11
Lifang Zhang, Taro Okada, Shaymaa Mohamed Mohamed Badawy, Chihoko Hirai, Taketoshi Kajimoto, Shun-Ichi Nakamura
Parkinson's disease (PD) is the second most common neurodegenerative disorder. The presence of α-synuclein (α-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies, is the cytopathological hallmark of PD. Increasing bodies of evidence suggest that cell-to-cell transmission of α-Syn plays a role in the progression of PD. Although extracellular α-Syn is known to cause abnormal cell motility, the precise mechanism remains elusive. Here we show that impairment of platelet-derived growth factor-induced cell motility caused by extracellular α-Syn is mainly attributed to selective inhibition of sphingosine 1-phosphate (S1P) signalling...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28223512/glucosylceramide-synthase-inhibition-alleviates-aberrations-in-synucleinopathy-models
#12
S Pablo Sardi, Catherine Viel, Jennifer Clarke, Christopher M Treleaven, Amy M Richards, Hyejung Park, Maureen A Olszewski, James C Dodge, John Marshall, Elina Makino, Bing Wang, Richard L Sidman, Seng H Cheng, Lamya S Shihabuddin
Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, Gba(D409V/D409V) and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28187263/tetrahydroxystilbene-glucoside-inhibits-%C3%AE-synuclein-aggregation-and-apoptosis-in-a53t-%C3%AE-synuclein-transfected-cells-exposed-to-mpp-sup-sup
#13
Ruyi Zhang, Fangling Sun, Lan Zhang, Xuejing Sun, Lin Li
Increasing evidence has solidified the involvement of α-synuclein (α-Syn) and neurotoxins in the pathogenesis of Parkinson's disease (PD), suggesting a combination of genetic and environmental influences. 2,3,5,4'-Tetrahydroxystilbene -2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. The purpose of the present study was to investigate the effects of TSG on α-Syn aggregation, mitochondrial dysfunction, oxidative stress and apoptosis in vitro. A53T mutant α-synuclein-transfected cells (A53T AS cells) plus MPP+<sup></sup> exposure were used as a complex cell model of PD...
February 10, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28143577/aav1-2-induced-overexpression-of-a53t-%C3%AE-synuclein-in-the-substantia-nigra-results-in-degeneration-of-the-nigrostriatal-system-with-lewy-like-pathology-and-motor-impairment-a-new-mouse-model-for-parkinson-s-disease
#14
Chi Wang Ip, Laura-Christin Klaus, Akua A Karikari, Naomi P Visanji, Jonathan M Brotchie, Anthony E Lang, Jens Volkmann, James B Koprich
α-Synuclein is a protein implicated in the etiopathogenesis of Parkinson's disease (PD). AAV1/2-driven overexpression of human mutated A53T-α-synuclein in rat and monkey substantia nigra (SN) induces degeneration of nigral dopaminergic neurons and decreases striatal dopamine and tyrosine hydroxylase (TH). Given certain advantages of the mouse, especially it being amendable to genetic manipulation, translating the AAV1/2-A53T α-synuclein model to mice would be of significant value. AAV1/2-A53T α-synuclein or AAV1/2 empty vector (EV) at a concentration of 5...
February 1, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28102321/the-chaperonin-cct-inhibits-assembly-of-%C3%AE-synuclein-amyloid-fibrils-by-a-specific-conformation-dependent-interaction
#15
Begoña Sot, Alejandra Rubio-Muñoz, Ahudrey Leal-Quintero, Javier Martínez-Sabando, Miguel Marcilla, Cintia Roodveldt, José M Valpuesta
The eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington's disease. This raises the possibility that CCT modulates other amyloidopathies, a still-unaddressed question. We show here that CCT inhibits amyloid fibre assembly of α-synuclein A53T, one of the mutants responsible for Parkinson's disease...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28053029/mutant-%C3%AE-synuclein-overexpression-induces-stressless-pacemaking-in-vagal-motoneurons-at-risk-in-parkinson-s-disease
#16
Efrat Lasser-Katz, Alon Simchovitz, Wei-Hua Chiu, Wolfgang H Oertel, Ronit Sharon, Hermona Soreq, Jochen Roeper, Joshua A Goldberg
α-Synuclein overexpression (ASOX) drives the formation of toxic aggregates in neurons vulnerable in Parkinson's disease (PD), including dopaminergic neurons of the substantia nigra (SN) and cholinergic neurons of the dorsal motor nucleus of the vagus (DMV). Just as these populations differ in when they exhibit α-synucleinopathies during PD pathogenesis, they could also differ in their physiological responses to ASOX. An ASOX-mediated hyperactivity of SN dopamine neurons, which was caused by oxidative dysfunction of Kv4...
January 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28012952/frontotemporal-dementia-as-the-presenting-phenotype-of-p-a53t-mutation-carriers-in-the-alpha-synuclein-gene
#17
Anastasia Bougea, Christos Koros, Maria Stamelou, Athina Simitsi, Nikolaos Papagiannakis, Roubina Antonelou, Dimitra Papadimitriou, Marianthi Breza, Konstantinos Tasios, Stella Fragkiadaki, Xenia Geronicola Trapali, Mara Bourbouli, Georgios Koutsis, Sokratis G Papageorgiou, Elisabeth Kapaki, George P Paraskevas, Leonidas Stefanis
INTRODUCTION: The p.A53T point mutation in SNCA, the alpha-synuclein gene, has been linked to a rare dominant form of Parkinson's disease (PD). METHODS: Here, we describe two apparently unrelated cases of p.A53T (G209A) SNCA mutation carriers with an atypical initial manifestation and disease course. Moreover, cerebrospinal fluid (CSF) levels of tau, p-tau and amyloid Aβ42 were measured in these patients and in an additional cohort of 5 symptomatic and 2 asymptomatic p...
December 6, 2016: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/27965467/microrna-expressing-profiles-in-a53t-mutant-alpha-synuclein-transgenic-mice-and-parkinsonian
#18
Mingshu Mo, Yousheng Xiao, Shuxuan Huang, Luan Cen, Xiang Chen, Limin Zhang, Qin Luo, Shaomin Li, Xinling Yang, Xian Lin, Pingyi Xu
α-synuclein gene mutations can cause α-synuclein protein aggregation in the midbrain of Parkinson's disease (PD) patients. MicroRNAs (miRNAs) play a key role in the metabolism of α-synuclein but the mechanism involved in synucleinopathy remains unclear. In this study, we investigated the miRNA profiles in A53T-α-synuclein transgenic mice and analyzed the candidate miRNAs in the cerebrospinal fluid (CSF) of PD patients. The 12-month A53T-transgenic mouse displayed hyperactive movement and anxiolytic-like behaviors with α-synuclein aggregation in midbrain...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/27919712/extracts-from-two-ubiquitous-mediterranean-plants-ameliorate-cellular-and-animal-models-of-neurodegenerative-proteinopathies
#19
Michelle Briffa, Stephanie Ghio, Johanna Neuner, Alison J Gauci, Rebecca Cacciottolo, Christelle Marchal, Mario Caruana, Christophe Cullin, Neville Vassallo, Ruben J Cauchi
A signature feature of age-related neurodegenerative proteinopathies is the misfolding and aggregation of proteins, typically amyloid-β (Aβ) in Alzheimer's disease (AD) and α-synuclein (α-syn) in Parkinson's disease (PD), into soluble oligomeric structures that are highly neurotoxic. Cellular and animal models that faithfully replicate the hallmark features of these disorders are being increasing exploited to identify disease-modifying compounds. Natural compounds have been identified as a useful source of bioactive molecules with promising neuroprotective capabilities...
December 2, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27902767/towards-a-non-human-primate-model-of-alpha-synucleinopathy-for-development-of-therapeutics-for-parkinson-s-disease-optimization-of-aav1-2-delivery-parameters-to-drive-sustained-expression-of-alpha-synuclein-and-dopaminergic-degeneration-in-macaque
#20
James B Koprich, Tom H Johnston, Gabriela Reyes, Vanessa Omana, Jonathan M Brotchie
Recent failures in clinical trials for disease modification in Parkinson's disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway...
2016: PloS One
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