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alpha synuclein and aggregation

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https://www.readbyqxmd.com/read/27927963/inhibition-of-prolyl-oligopeptidase-restores-spontaneous-motor-behavior-in-the-%C3%AE-synuclein-virus-vector-based-parkinson-s-disease-mouse-model-by-decreasing-%C3%AE-synuclein-oligomeric-species-in-mouse-brain
#1
Reinis Svarcbahs, Ulrika H Julku, Timo T Myöhänen
: Decreased clearance of α-synuclein (aSyn) and aSyn protein misfolding and aggregation are seen as major factors in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies that leads to disruption in neuronal function and eventually to cell death. Prolyl oligopeptidase (PREP) can accelerate the aSyn aggregation process, while inhibition of PREP by a small molecule inhibitor decreases aSyn oligomer formation and enhances its clearance via autophagy in different aSyn overexpressing cell types and in transgenic PD animal models...
December 7, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27926845/membrane-bound-alpha-synuclein-clusters-induce-impaired-lipid-diffusion-and-increased-lipid-packing
#2
Aditya Iyer, Nathalie Schilderink, Mireille M A E Claessens, Vinod Subramaniam
The aggregation of membrane-bound α-synuclein (αS) into oligomers and/or amyloid fibrils has been suggested to cause membrane damage in in vitro model phospholipid membrane systems and in vivo. In this study, we investigate how αS interactions that precede the formation of well-defined aggregates influence physical membrane properties. Using three truncated variants of αS with different aggregation propensities and comparable phospholipid membrane binding affinities we show, using fluorescence recovery after photobleaching (FRAP) and fluorescence anisotropy measurements, that formation of αS clusters on supported lipid bilayers (SLBs) impairs lateral lipid diffusion and increases lipid packing beneath the αS clusters...
December 6, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27917933/inhibition-of-alpha-synuclein-aggregation-by-multifunctional-dopamine-agonists-assessed-by-a-novel-in-vitro-assay-and-an-in-vivo-drosophila-synucleinopathy-model
#3
Deepthi Yedlapudi, Gnanada S Joshi, Dan Luo, Sokol V Todi, Aloke K Dutta
Aggregation of alpha synuclein (α-syn) leading to dopaminergic neuronal death has been recognized as one of the main pathogenic factors in the initiation and progression of Parkinson's disease (PD). Consequently, α-syn has been targeted for the development of therapeutics for PD. We have developed a novel assay to screen compounds with α-syn modulating properties by mimicking recent findings from in vivo animal studies involving intrastriatal administration of pre-formed fibrils in mice, resulting in increased α-syn pathology accompanying the formation of Lewy-body (LB) type inclusions...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27916677/differential-copper-binding-to-alpha-synuclein-and-its-disease-associated-mutants-affect-the-aggregation-and-amyloid-formation
#4
Priyatosh Ranjan, Dhiman Ghosh, Deepthi S Yarramala, Subhadeep Das, Samir K Maji, Ashutosh Kumar
BACKGROUND: Copper is an essential trace element required for the proper functioning of various enzymes present in central nervous system. An imbalance in the copper homeostasis results in the pathology of various neurogenerative disorders including Parkinson's Disease. Hence, residue specific interaction of Cu(2+) to α-Syn along with the familial mutants H50Q and G51D needs to be studied in detail. METHODS: We investigated the residue specific mapping of Cu(2+) binding sites and binding strength using solution-state NMR and ITC respectively...
December 1, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27904575/alpha-synuclein-structure-functions-and-interactions
#5
REVIEW
Fatemeh Nouri Emamzadeh
At present, when a clinical diagnosis of Parkinson's disease (PD) is made, serious damage has already been done to nerve cells of the substantia nigra pars compacta. The diagnosis of PD in its earlier stages, before this irreversible damage, would be of enormous benefit for future treatment strategies designed to slow or halt the progression of this disease that possibly prevents accumulation of toxic aggregates. As a molecular biomarker for the detection of PD in its earlier stages, alpha-synuclein (α-syn), which is a key component of Lewy bodies, in which it is found in an aggregated and fibrillar form, has attracted considerable attention...
2016: Journal of Research in Medical Sciences: the Official Journal of Isfahan University of Medical Sciences
https://www.readbyqxmd.com/read/27901068/nanomechanical-properties-of-distinct-fibrillar-polymorphs-of-the-protein-%C3%AE-synuclein
#6
Ali Makky, Luc Bousset, Jérôme Polesel-Maris, Ronald Melki
Alpha-synuclein (α-Syn) is a small presynaptic protein of 140 amino acids. Its pathologic intracellular aggregation within the central nervous system yields protein fibrillar inclusions named Lewy bodies that are the hallmarks of Parkinson's disease (PD). In solution, pure α-Syn adopts an intrinsically disordered structure and assembles into fibrils that exhibit considerable morphological heterogeneity depending on their assembly conditions. We recently established tightly controlled experimental conditions allowing the assembly of α-Syn into highly homogeneous and pure polymorphs...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27896833/exploiting-the-aggregation-properties-of-alpha-synuclein-for-diagnostic-purposes
#7
David P Breen, Lorraine V Kalia
No abstract text is available yet for this article.
November 29, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27893183/toxic-effects-of-human-and-rodent-variants-of-alpha-synuclein-in-vivo
#8
Natalie Landeck, Kerstin Buck, Deniz Kirik
In Parkinson's disease, abnormal alpha-synuclein (asyn) accumulation leads to the formation of soluble oligomeric species thought to be toxic to cells as well as intraneuronal inclusions. To date, the precise mechanisms leading to aggregation of asyn in the brain is not well understood. Previous studies in yeast, drosophila and transgenic mice suggested that a non-A beta component depleted version of human asyn [h-asyn(D70-83)] or human beta-synuclein (h-bsyn), naturally lacking this centrally located hydrophobic region, are less prone to form aggregates in vitro and are expected to be less toxic compared to h-asyn in vivo, although not all experimental studies unequivocally support the latter view...
November 28, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27853754/commentary-alpha-synuclein-interacts-with-sod1-and-promotes-its-oligomerization
#9
Anika M Helferich, Pamela J McLean, Jochen H Weishaupt, Karin M Danzer
Alpha-synuclein and Cu, Zn superoxide dismutase (SOD1) are both aggregation-prone proteins that are associated with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), respectively. Recently, we showed that alpha-synuclein interacts with SOD1 in various cell types and tissues. Using a cell culture model, we also found that alpha-synuclein nucleates the polymerization of SOD1. Here, we discuss the current literature regarding their interaction and their co-localization in aggregates of human post-mortem tissue...
2016: Journal of Neurology & Neuromedicine
https://www.readbyqxmd.com/read/27853185/phosphorylation-induces-distinct-alpha-synuclein-strain-formation
#10
Meng-Rong Ma, Zhi-Wen Hu, Yu-Fen Zhao, Yong-Xiang Chen, Yan-Mei Li
Synucleinopathies are a group of neurodegenerative diseases associated with alpha-synuclein (α-Syn) aggregation. Recently, increasing evidence has demonstrated the existence of different structural characteristics or 'strains' of α-Syn, supporting the concept that synucleinopathies share several common features with prion diseases and possibly explaining how a single protein results in different clinical phenotypes within synucleinopathies. In earlier studies, the different strains were generated through the regulation of solution conditions, temperature, or repetitive seeded fibrillization in vitro...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27837450/subcellular-parkinson-s-disease-specific-alpha-synuclein-species-show-altered-behavior-in-neurodegeneration
#11
Rashed Abdullah, Ketan S Patil, Benjamin Rosen, Ramavati Pal, Shubhangi Prabhudesai, Sungsu Lee, Indranil Basak, Esthelle Hoedt, Peter Yang, Keith Panick, Hsin-Pin Ho, Emmanuel Chang, Charalampos Tzoulis, Jan Petter Larsen, Thomas A Neubert, Guido Alves, Simon G Møller
Parkinson's disease and other synucleinopathies are characterized by the presence of intra-neuronal protein aggregates enriched in the presynaptic protein α-synuclein. α-synuclein is considered an intrinsically disordered 14 kDa monomer, and although poorly understood, its transition to higher-order multimeric species may play central roles in healthy neurons and during Parkinson's disease pathogenesis. In this study, we demonstrate that α-synuclein exists as defined, subcellular-specific species that change characteristics in response to oxidative stress in neuroblastoma cells and in response to Parkinson's disease pathogenesis in human cerebellum and frontal cortex...
November 11, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27818354/prolyl-oligopeptidase-inhibition-attenuates-the-toxicity-of-a-proteasomal-inhibitor-lactacystin-in-the-alpha-synuclein-overexpressing-cell-culture
#12
Timo T Myöhänen, Susanna Norrbacka, Mari H Savolainen
Lewy bodies, the histopathological hallmarks of Parkinson's disease (PD), contain insoluble and aggregated α-synuclein (aSyn) and many other proteins, proposing a role for failure in protein degradation system in the PD pathogenesis. Proteasomal dysfunction has indeed been linked to PD and aSyn oligomers have been shown to inhibit proteasomes and autophagy. Our recent studies have shown that inhibitors of prolyl oligopeptidase (PREP) can prevent the aggregation and enhance the clearance of accumulated aSyn, and therefore, we wanted to study if PREP inhibition can overcome the aSyn aggregation and toxicity induced by lactacystin, a proteasomal inhibitor...
January 1, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/27769419/combined-in-situ-imaging-of-structural-organization-and-elemental-composition-of-substantia-nigra-neurons-in-the-elderly
#13
A D Surowka, M Töpperwien, M Bernhardt, J D Nicolas, M Osterhoff, T Salditt, D Adamek, M Szczerbowska-Boruchowska
Human dopaminergic system in general, and substantia nigra (SN) neurons, in particular, are implicated in the pathologies underlying the human brain aging. The interplay between aberrations in the structural organization and elemental composition of SN neuron bodies has recently gained in importance as selected metals: Fe, Cu, Zn, Ca were found to trigger oxidative-stress-mediated aberration in their molecular assembly due to concomitant protein (alpha-synuclein, tau-protein) aggregation, gliosis and finally oxidative stress...
December 1, 2016: Talanta
https://www.readbyqxmd.com/read/27752516/alpha-synuclein-rt-quic-in-the-csf-of-patients-with-alpha-synucleinopathies
#14
Graham Fairfoul, Lynne I McGuire, Suvankar Pal, James W Ironside, Juliane Neumann, Sharon Christie, Catherine Joachim, Margaret Esiri, Samuel G Evetts, Michal Rolinski, Fahd Baig, Claudio Ruffmann, Richard Wade-Martins, Michele T M Hu, Laura Parkkinen, Alison J E Green
We have developed a novel real-time quaking-induced conversion RT-QuIC-based assay to detect alpha-synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and Parkinson's disease patients. This assay can detect alpha-synuclein aggregation in Dementia with Lewy bodies and Parkinson's disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results...
October 2016: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/27746320/alpha-synuclein-aggregates-are-excluded-from-calbindin-d28k-positive-neurons-in-dementia-with-lewy-bodies-and-a-unilateral-rotenone-mouse-model
#15
Alexandre N Rcom-H'cheo-Gauthier, Amelia Davis, Adrian C B Meedeniya, Dean L Pountney
α-Synuclein (α-syn) aggregates (Lewy bodies) in Dementia with Lewy Bodies (DLB) may be associated with disturbed calcium homeostasis and oxidative stress. We investigated the interplay between α-syn aggregation, expression of the calbindin-D28k (CB) neuronal calcium-buffering protein and oxidative stress, combining immunofluorescence double labelling and Western analysis, and examining DLB and normal human cases and a unilateral oxidative stress lesion model of α-syn disease (rotenone mouse). DLB cases showed a greater proportion of CB+ cells in affected brain regions compared to normal cases with Lewy bodies largely present in CB- neurons and virtually undetected in CB+ neurons...
December 2016: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/27733604/monomeric-alpha-synuclein-exerts-a-physiological-role-on-brain-atp-synthase
#16
Marthe H R Ludtmann, Plamena R Angelova, Natalia N Ninkina, Sonia Gandhi, Vladimir L Buchman, Andrey Y Abramov
: Misfolded α-synuclein is a key factor in the pathogenesis of Parkinson's disease (PD). However, knowledge about a physiological role for the native, unfolded α-synuclein is limited. Using brains of mice lacking α-, β-, and γ-synuclein, we report that extracellular monomeric α-synuclein enters neurons and localizes to mitochondria, interacts with ATP synthase subunit α, and modulates ATP synthase function. Using a combination of biochemical, live-cell imaging and mitochondrial respiration analysis, we found that brain mitochondria of α-, β-, and γ-synuclein knock-out mice are uncoupled, as characterized by increased mitochondrial respiration and reduced mitochondrial membrane potential...
October 12, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27720003/epidemiology-of-parkinson-disease
#17
Andrea Lee, Rebecca M Gilbert
Parkinson disease (PD) is a common progressive neurodegenerative condition, causing both motor and non motor symptoms. Motor symptoms include stiffness, slowness, rest tremor and poor postural reflexes, whereas nonmotor symptoms include abnormalities of mood, cognition, sleep and autonomic function. Affected patients show cell loss in the substantia nigra pars compacta, and accumulation of aggregated alpha-synuclein into intracellular structures called Lewy bodies, within specific brain regions. The main known non modifiable risk factor is age...
November 2016: Neurologic Clinics
https://www.readbyqxmd.com/read/27711049/clozapine-modulates-glucosylceramide-clears-aggregated-proteins-and-enhances-atg8-lc3-in-caenorhabditis-elegans
#18
Limin Hao, Oshrit Ben-David, Suzann M Babb, Anthony H Futerman, Bruce M Cohen, Edgar A Buttner
Defining the mechanisms of action of the antipsychotic drug (APD), clozapine, is of great importance, as clozapine is more effective and has therapeutic benefits in a broader range of psychiatric disorders compared with other APDs. Its range of actions have not been fully characterized. Exposure to APDs early in development causes dose-dependent developmental delay and lethality in Caenorhabditis elegans. A previous genome-wide RNAi screen for suppressors of clozapine-induced developmental delay and lethality revealed 40 candidate genes, including sms-1, which encodes a sphingomyelin synthase...
October 26, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27708338/exposure-to-the-functional-bacterial-amyloid-protein-curli-enhances-alpha-synuclein-aggregation-in-aged-fischer-344-rats-and-caenorhabditis-elegans
#19
Shu G Chen, Vilius Stribinskis, Madhavi J Rane, Donald R Demuth, Evelyne Gozal, Andrew M Roberts, Rekha Jagadapillai, Ruolan Liu, Kyonghwan Choe, Bhooma Shivakumar, Francheska Son, Shunying Jin, Richard Kerber, Anthony Adame, Eliezer Masliah, Robert P Friedland
Misfolded alpha-synuclein (AS) and other neurodegenerative disorder proteins display prion-like transmission of protein aggregation. Factors responsible for the initiation of AS aggregation are unknown. To evaluate the role of amyloid proteins made by the microbiota we exposed aged rats and transgenic C. elegans to E. coli producing the extracellular bacterial amyloid protein curli. Rats exposed to curli-producing bacteria displayed increased neuronal AS deposition in both gut and brain and enhanced microgliosis and astrogliosis compared to rats exposed to either mutant bacteria unable to synthesize curli, or to vehicle alone...
October 6, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27706423/aged-lewis-rats-exposed-to-low-and-moderate-doses-of-rotenone-are-a-good-model-for-studying-the-process-of-protein-aggregation-and-its-effects-upon-central-nervous-system-cell-physiology
#20
Michael F Almeida, Carolliny M Silva, Aline M D'Unhao, Merari F R Ferrari
Cell physiology is impaired before protein aggregation and this may be more relevant than inclusions themselves for neurodegeneration. The present study aimed to characterize an animal model to enable the analysis of the cell biology before and after protein aggregation. Ten-month-old Lewis rats were exposed either to 1 or 2 mg/kg/day of rotenone, delivered subcutaneously through mini-pumps, for one month. Hyperphosphorylated TAU, alpha-synuclein, amyloid-beta peptide and protein carbonylation (indicative of oxidative stress) were evaluated in the hippocampus, substantia nigra and locus coeruleus through immunohistochemistry or western blot...
September 2016: Arquivos de Neuro-psiquiatria
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