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synuclein and aggregation

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https://www.readbyqxmd.com/read/28092083/role-of-dopamine-d2-d3-receptors-in-development-plasticity-and-neuroprotection-in-human-ipsc-derived-midbrain-dopaminergic-neurons
#1
Federica Bono, Paola Savoia, Adele Guglielmi, Massimo Gennarelli, Giovanna Piovani, Sandra Sigala, Damiana Leo, Stefano Espinoza, Raul R Gainetdinov, Paola Devoto, PierFranco Spano, Cristina Missale, Chiara Fiorentini
The role of dopamine D2 and D3 receptors (D2R/D3R), located on midbrain dopaminergic (DA) neurons, in the regulation of DA synthesis and release and in DA neuron homeostasis has been extensively investigated in rodent animal models. By contrast, the properties of D2R/D3R in human DA neurons have not been elucidated yet. On this line, the use of human-induced pluripotent stem cells (hiPSCs) for producing any types of cells has offered the innovative opportunity for investigating the human neuronal phenotypes at the molecular levels...
January 14, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28075555/familial-mutations-may-switch-conformational-preferences-in-%C3%AE-synuclein-fibrils
#2
Liang Xu, Buyong Ma, Ruth Nussinov, Damien Thompson
The pathogenesis of Parkinson's disease is closely associated with the aggregation of the α-synuclein protein. Several familial mutants have been identified and shown to affect the aggregation kinetics of α-synuclein through distinct molecular mechanisms. Quantitative evaluation of the relative stabilities of the wild type and mutant fibrils is crucial for understanding the aggregation process and identifying the key component steps. In this work, we examined two topologically different α-synuclein fibril structures that are either determined by solid-state NMR method or modelled based on solid-state NMR data, and characterized their conformational properties and thermodynamic stabilities using molecular dynamics simulations...
January 11, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28069058/endosulfine-alpha-inhibits-membrane-induced-%C3%AE-synuclein-aggregation-and-protects-against-%C3%AE-synuclein-neurotoxicity
#3
Daniel Ysselstein, Benjamin Dehay, Isabel M Costantino, George P McCabe, Matthew P Frosch, Julia M George, Erwan Bezard, Jean-Christophe Rochet
Neuropathological and genetic findings suggest that the presynaptic protein α-synuclein (aSyn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of aSyn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in aSyn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces...
January 10, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28068606/trehalose-does-not-improve-neuronal-survival-on-exposure-to-alpha-synuclein-pre-formed-fibrils
#4
Matthew Redmann, Willayat Y Wani, Laura Volpicelli-Daley, Victor Darley-Usmar, Jianhua Zhang
Parkinson's disease is a debilitating neurodegenerative disorder that is pathologically characterized by intracellular inclusions comprised primarily of alpha-synuclein (αSyn) that can also be transmitted from neuron to neuron. Several lines of evidence suggest that these inclusions cause neurodegeneration. Thus exploring strategies to improve neuronal survival in neurons with αSyn aggregates is critical. Previously, exposure to αSyn pre-formed fibrils (PFFs) has been shown to induce aggregation of endogenous αSyn resulting in cell death that is exacerbated by either starvation or inhibition of mTOR by rapamycin, both of which are able to induce autophagy, an intracellular protein degradation pathway...
January 3, 2017: Redox Biology
https://www.readbyqxmd.com/read/28057080/combination-of-alpha-synuclein-immunotherapy-with-anti-inflammatory-treatment-in-a-transgenic-mouse-model-of-multiple-system-atrophy
#5
Elvira Valera, Brian Spencer, Jerel A Fields, Ivy Trinh, Anthony Adame, Michael Mante, Edward Rockenstein, Paula Desplats, Eliezer Masliah
Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the pathological accumulation of alpha-synuclein (α-syn) in oligodendrocytes. Therapeutic efforts to stop or delay the progression of MSA have yielded suboptimal results in clinical trials, and there are no efficient treatments currently available for MSA patients. We hypothesize that combining therapies targeting different aspects of the disease may lead to better clinical outcomes. To test this hypothesis, we combined the use of a single-chain antibody targeting α-syn modified for improved central nervous system penetration (CD5-D5) with an unconventional anti-inflammatory treatment (lenalidomide) in the myelin basic protein (MBP)-α-syn transgenic mouse model of MSA...
January 5, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28057070/distinct-pattern-of-enteric-phospho-alpha-synuclein-aggregates-and-gene-expression-profiles-in-patients-with-parkinson-s-disease
#6
Martina Barrenschee, Dimitri Zorenkov, Martina Böttner, Christina Lange, François Cossais, Amelie Bernadette Scharf, Günther Deuschl, Susanne A Schneider, Mark Ellrichmann, Annette Fritscher-Ravens, Thilo Wedel
Phosphorylated alpha-synuclein (p-α-syn) containing Lewy bodies (LBs) and Lewy neurites (LNs) are neuropathological hallmarks of Parkinson's disease (PD) in the central nervous system (CNS). Since they have been also demonstrated in the enteric nervous system (ENS) of PD patients, the aim of the study was to analyze enteric p-α-syn positive aggregates and intestinal gene expression. Submucosal rectal biopsies were obtained from patients with PD and controls and processed for dual-label-immunohistochemistry for p-α-syn and PGP 9...
January 5, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28056734/metal-nanoparticles-for-the-treatment-and-diagnosis-of-neurodegenerative-brain-diseases
#7
Valentina Vio, María José Marchant, Eyleen Araya, Marcelo J Kogan
This review focuses on the application of metal nanoparticles in the diagnosis and treatment of Alzheimer's and Parkinson's diseases. Metal nanoparticles present interesting physicochemical properties that can be applied to increase biomarker detection sensitivities in vitro and in vivo. Furthermore, these nanoparticles could be used in different strategies for the treatment of central nervous system diseases, particularly in regards to drug delivery. Herein, specific potential applications of metal nanoparticles are separately discussed for the contexts of in vitro diagnoses and treatments...
January 5, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28053029/mutant-%C3%AE-synuclein-overexpression-induces-stressless-pacemaking-in-vagal-motoneurons-at-risk-in-parkinson-s-disease
#8
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/28045494/site-specific-fluorescence-polarization-for-studying-the-disaggregation-of-%C3%AE-synuclein-fibrils-by-small-molecules
#9
Conor M Haney, Christina L Cleveland, Rebecca F Wissner, Lily Owei, Jaclyn Robustelli, Malcolm J Daniels, Merve Canyurt, Priscilla Rodriguez, Harry Ischiropoulos, Tobias Baumgart, E James Petersson
Fibrillar aggregates of the protein α-synuclein (αS) are one of the hallmarks of Parkinson's disease. Here, we show that measuring the fluorescence polarization (FP) of labels at several sites on αS allows one to monitor changes in the local dynamics of the protein after binding to micelles or vesicles, and during fibril formation. Most significantly, these site-specific FP measurements provide insight into structural remodeling of αS fibrils by small molecules and have the potential for use in moderate-throughput screens to identify small molecules that could be used to treat Parkinson's disease...
November 11, 2016: Biochemistry
https://www.readbyqxmd.com/read/28031465/aggregation-of-full-length-immunoglobulin-light-chains-from-al-amyloidosis-patients-is-remodeled-by-epigallocatechin-3-gallate
#10
Kathrin Andrich, Ute Hegenbart, Christoph Kimmich, Niraja Kedia, H Robert Bergen, Stefan Schönland, Erich E Wanker, Jan Bieschke
Intervention into amyloid deposition with anti-amyloid agents like the polyphenol Epigallocatechin-3-gallate (EGCG) is emerging as an experimental secondary treatment strategy in systemic light chain amyloidosis (AL). In both AL and Multiple Myeloma (MM), soluble immunoglobulin light chains (LC) are produced by clonal plasma cells, but only in AL they form amyloid deposits in vivo. We investigated the amyloid formation of patient-derived LC and their susceptibility to EGCG in vitro to probe commonalities and systematic differences in their assembly mechanisms...
December 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28030591/aggregated-alpha-synuclein-transfer-efficiently-between-cultured-human-neuron-like-cells-and-localize-to-lysosomes
#11
Jakob Domert, Christopher Sackmann, Emelie Severinsson, Lotta Agholme, Joakim Bergström, Martin Ingelsson, Martin Hallbeck
Parkinson's disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells...
2016: PloS One
https://www.readbyqxmd.com/read/28028735/mapping-of-surface-exposed-epitopes-of-in-vitro-and-in-vivo-aggregated-species-of-alpha-synuclein
#12
Leire Almandoz-Gil, Veronica Lindström, Jessica Sigvardson, Philipp J Kahle, Lars Lannfelt, Martin Ingelsson, Joakim Bergström
Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal deposits observed in Parkinson's disease and dementia with Lewy bodies. The objective of the study was to identify surface-exposed epitopes of alpha-synuclein in vitro and in vivo formed aggregates. Polyclonal immunoglobulin Y antibodies were raised against short linear peptides of the alpha-synuclein molecule. An epitope in the N-terminal region (1-10) and all C-terminal epitopes (90-140) were found to be exposed in an indirect enzyme-linked immunosorbent assay (ELISA) using recombinant monomeric, oligomeric, and fibrillar alpha-synuclein...
December 27, 2016: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/28025780/exosomes-in-parkinson-s-disease
#13
REVIEW
Xiaoqing Wu, Tingting Zheng, Baorong Zhang
Exosomes, nano-sized extracellular vesicles secreted by most cell types, are found in all kinds of biological fluids and tissues, including the central nervous system (CNS). The proposed functions of these vesicles include roles in cell-cell signaling, removal of cellular debris, and transfer of pathogens between cells. Many studies have revealed that exosomes derived from the CNS occur in the cerebrospinal fluid and peripheral body fluids, and their contents are altered during disease, making them an appealing target for biomarker development in Parkinson's disease (PD)...
December 26, 2016: Neuroscience Bulletin
https://www.readbyqxmd.com/read/28024449/effects-of-different-force-fields-on-the-structural-character-of-%C3%AE-synuclein-%C3%AE-hairpin-peptide-35-56-in-aqueous-environment
#14
Sangeeta Kundu
The hallmark of Parkinson's disease (PD) is the intracellular protein aggregation forming Lewy Bodies (LB) and Lewy neuritis which comprise mostly of a protein, alpha synuclein (α-syn). Molecular dynamics (MD) simulation methods can augment experimental techniques to understand misfolding and aggregation pathways with atomistic resolution. The quality of MD simulations for proteins and peptides depends greatly on the accuracy of empirical force fields. The aim of this work is to investigate the effects of different force fields on the structural character of β hairpin fragment of α-syn (residues 35-56) peptide in aqueous solution...
December 26, 2016: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28007442/analysis-of-sheep-%C3%AE-synuclein-provides-a-molecular-strategy-for-the-reduction-of-fibrillation
#15
Lungisa Bickle, John J Hopwood, Litsa Karageorgos
Parkinson's disease (PD) presents with neuropathological inclusions called Lewy bodies, which are primarily composed of fibrillar α-synuclein. Recently, we characterized sheep with Gaucher disease and since GBA1 mutations represent the highest genetic risk factor for PD, we have investigated α-synuclein fibrillation in the sheep. Here we demonstrate that differences in six amino acid residues between sheep and human α-synuclein significantly alter in vitro fibril formation. Circular dichroism of recombinant human and sheep α-synuclein show that both proteins adopt the same secondary structure...
December 19, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28004858/new-evidence-comes-to-light-how-is-%C3%AE-synuclein-aggregation-related-to-mitochondrial-protein-import-in-parkinson-s-disease
#16
Farzaneh Rahmani, Aida Kamalian, Mohammad Hadi Aarabi
No abstract text is available yet for this article.
December 22, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28004278/histones-facilitate-%C3%AE-synuclein-aggregation-during-neuronal-apoptosis
#17
Peizhou Jiang, Ming Gan, Shu-Hui Yen, Pamela J McLean, Dennis W Dickson
Ample in vitro and in vivo experimental evidence supports the hypothesis that intercellular transmission of α-synuclein (αS) is a mechanism underlying the spread of αS pathology in Parkinson's disease and related disorders. What remains unexplained is where and how initial transmissible αS aggregates form. In a previous study, we demonstrated that αS aggregates rapidly form in neurons with impaired nuclear membrane integrity due to the interaction between nuclear proaggregant factor(s) and αS and that such aggregates may serve as a source for αS seeding...
December 21, 2016: Acta Neuropathologica
https://www.readbyqxmd.com/read/27997702/impulse-control-disorder-lysosomal-malfunction-and-atp13a2-insufficiency-in-parkinsonism
#18
REVIEW
Jun-Ping Liu, Jianfeng Li, Yanhua Lu, Lihui Wang, Gang Chen
Lysosomal transport of cargos in neurons is essential for neuronal proteostasis, transmission and functional motors and behaviors. Lysosomal malfunction including storage disorders is involved in the pathogenesis of Parkinson's disease (PD). Given the unclear molecular mechanisms of diverse defects in PD phenotypes, especially behavioral deficits, this mini review explores the cellular contexts of PD impulse control disorders and the molecular aspects of lysosomal cross-membrane transports. Focuses are paid to trace metal involvements in α-synuclein assembly in Lewy bodies, the functions and molecular interactions of ATP13A2 as ATPase transporters in lysosomal membranes for cross-membrane trafficking and lysosomal homeostasis, and our current understandings of the neural circuits in ICD...
December 20, 2016: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/27997067/rotenone-and-elevated-extracellular-potassium-concentration-induce-cell-specific-fibrillation-of-%C3%AE-synuclein-in-axons-of-cholinergic-enteric-neurons-in-the-guinea-pig-ileum
#19
D F Sharrad, B N Chen, W P Gai, N Vaikath, O M El-Agnaf, S J H Brookes
BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder that results in the widespread loss of select classes of neurons throughout the nervous system. The pathological hallmarks of Parkinson's disease are Lewy bodies and neurites, of which α-synuclein fibrils are the major component. α-Synuclein aggregation has been reported in the gut of Parkinson's disease patients, even up to a decade before motor symptoms, and similar observations have been made in animal models of disease...
November 7, 2016: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
https://www.readbyqxmd.com/read/27993598/role-of-neurotoxicants-and-traumatic-brain-injury-in-%C3%AE-synuclein-protein-misfolding-and-aggregation
#20
Dharmin Rokad, Shivani Ghaisas, Dilshan S Harischandra, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy
Protein misfolding and aggregation are key pathological features of many neurodegenerative diseases including Parkinson's disease (PD) and other forms of human Parkinsonism. PD is a complex and multifaceted disorder whose etiology is not fully understood. However, several lines of evidence support the multiple hit hypothesis that genetic vulnerability and environmental toxicants converge to trigger PD pathology. Alpha-synuclein (α-Syn) aggregation in the brain is an important pathophysiological characteristic of synucleinopathies including PD...
December 16, 2016: Brain Research Bulletin
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