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Alpha-synuclein

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https://www.readbyqxmd.com/read/29467608/understanding-the-role-of-adenosine-a2ar-heteroreceptor-complexes-in-neurodegeneration-and-neuroinflammation
#1
Dasiel O Borroto-Escuela, Sonja Hinz, Gemma Navarro, Rafael Franco, Christa E Müller, Kjell Fuxe
Adenosine is a nucleoside mainly formed by degradation of ATP, located intracellularly or extracellularly, and acts as a neuromodulator. It operates as a volume transmission signal through diffusion and flow in the extracellular space to modulate the activity of both glial cells and neurons. The effects of adenosine are mediated via four adenosine receptor subtypes: A1R, A2AR, A2BR, A3R. The A2AR has a wide-spread distribution but it is especially enriched in the ventral and dorsal striatum where it is mainly located in the striato-pallidal GABA neurons at a synaptic and extrasynaptic location...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29459819/ganglioside-metabolism-and-parkinson-s-disease
#2
John Forsayeth, Piotr Hadaczek
Here we advance the hypothesis that Parkinson's disease (PD) is fundamentally a failure of trophic support for specific classes of neurons, primarily catecholaminergic. Evidence from our laboratory provides a framework into which a broad array of findings from many quarters can be integrated into a general theory that offers testable hypotheses to new and established investigators. Mice deficient in the ability to synthesize series-a gangliosides, specifically GM1 ganglioside, develop parkinsonism. We found that this seems to be due to a failure in signaling efficiency by the important catecholaminergic growth factor, GDNF...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29459792/c-terminal-calcium-binding-of-%C3%AE-synuclein-modulates-synaptic-vesicle-interaction
#3
Janin Lautenschläger, Amberley D Stephens, Giuliana Fusco, Florian Ströhl, Nathan Curry, Maria Zacharopoulou, Claire H Michel, Romain Laine, Nadezhda Nespovitaya, Marcus Fantham, Dorothea Pinotsi, Wagner Zago, Paul Fraser, Anurag Tandon, Peter St George-Hyslop, Eric Rees, Jonathan J Phillips, Alfonso De Simone, Clemens F Kaminski, Gabriele S Kaminski Schierle
Alpha-synuclein is known to bind to small unilamellar vesicles (SUVs) via its N terminus, which forms an amphipathic alpha-helix upon membrane interaction. Here we show that calcium binds to the C terminus of alpha-synuclein, therewith increasing its lipid-binding capacity. Using CEST-NMR, we reveal that alpha-synuclein interacts with isolated synaptic vesicles with two regions, the N terminus, already known from studies on SUVs, and additionally via its C terminus, which is regulated by the binding of calcium...
February 19, 2018: Nature Communications
https://www.readbyqxmd.com/read/29458199/alpha-synuclein-oligomers-impair-memory-through-glial-cell-activation-and-via-toll-like-receptor-2
#4
Pietro La Vitola, Claudia Balducci, Milica Cerovic, Giulia Santamaria, Edoardo Brandi, Federica Grandi, Laura Caldinelli, Laura Colombo, Maria Grazia Morgese, Luigia Trabace, Loredano Pollegioni, Diego Albani, Gianluigi Forloni
Alpha-synuclein oligomers (α-synOs) are emerging as crucial factors in the pathogenesis of synucleinopathies. Although the connection between neuroinflammation and α-syn still remains elusive, increasing evidence suggests that extracellular moieties activate glial cells leading to neuronal damage. Using an acute mouse model, we explored whether α-synOs induce memory impairment in association to neuroinflammation, addressing Toll-like receptors 2 and 4 (TLR2 and TLR4) involvement. We found that α-synOs abolished mouse memory establishment in association to hippocampal glial activation...
February 16, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29455934/corrigendum-to-low-molar-excess-of-4-oxo-2-nonenal-and-4-hydroxy-2-nonenal-promote-oligomerization-of-alpha-synuclein-through-different-pathways-free-rad-biol-med-2017-421-431
#5
Leire Almandoz-Gil, Hedvig Welander, Elisabeth Ihse, Payam Emami Khoonsari, Sravani Musunuri, Christofer Lendel, Jessica Sigvardson, Mikael Karlsson, Martin Ingelsson, Kim Kultima, Joakim Bergström
No abstract text is available yet for this article.
February 15, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29452354/alpha-synuclein-inhibits-snx3-retromer-mediated-retrograde-recycling-of-iron-transporters-in-s-cerevisiae-and-c-elegans-models-of-parkinson-s-disease
#6
Dhaval Patel, Chuan Xu, Sureshbabu Nagarajan, Zhengchang Liu, Wayne O Hemphill, Runhua Shi, Vladimir N Uversky, Guy A Caldwell, Kim A Caldwell, Stephan N Witt
We probed the role of alpha-synuclein (α-syn) in modulating sorting nexin 3 (Snx3)-retromer-mediated recycling of iron transporters in Saccharomyces cerevisiae and Caenorhabditis elegans. In yeast, the membrane-bound heterodimer Fet3/Ftr1 is the high affinity iron importer. Fet3 is a membrane-bound multicopper ferroxidase, whose ferroxidase domain is orthologous to human ceruloplasmin (Cp), that oxidizes external Fe+2 to Fe+3; the Fe+3 ions then channel through the Ftr1 permease into the cell. When the concentration of external iron is low (< 1 µM), Fet3/Ftr1 is maintained on the plasma membrane by retrograde endocytic-recycling; whereas, when the concentration of external iron is high (> 10 µM), Fet3/Ftr1 is endocytosed and shunted to the vacuole for degradation...
February 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29433982/bimolecular-fluorescence-complementation-of-alpha-synuclein-demonstrates-its-oligomerization-with-dopaminergic-phenotype-in-mice
#7
Waijiao Cai, Danielle Feng, Michael A Schwarzschild, Pamela J McLean, Xiqun Chen
Alpha-synuclein (αSyn) is encoded by the first causal gene identified in Parkinson's disease (PD) and is the main component of Lewy bodies, a pathological hallmark of PD. aSyn-based animal models have contributed to our understanding of PD pathophysiology and to the development of therapeutics. Overexpression of human wildtype αSyn by viral vectors in rodents recapitulates the loss of dopaminergic neurons from the substantia nigra, another defining pathological feature of the disease. The development of a rat model exhibiting bimolecular fluorescence complementation (BiFC) of αSyn by recombinant adeno-associated virus facilitates detection of the toxic αSyn oligomers species...
January 31, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29432756/region-and-cell-specific-aneuploidy-in-brain-aging-and-neurodegeneration
#8
REVIEW
C E Shepherd, Y Yang, G M Halliday
Variations in genomic DNA content, or aneuploidy, are a well-recognized feature of normal human brain development. Whether changes in the levels of aneuploidy are a factor in Alzheimer's disease (AD) is less clear, as the data reported to date vary substantially in the levels of aneuploidy detected (0.7-11.5%), possibly due to methodological limitations, but also influenced by individual, regional and cellular heterogeneity as well as variations in cell subtypes. These issues have not been adequately addressed to date...
February 9, 2018: Neuroscience
https://www.readbyqxmd.com/read/29429047/the-small-gtpase-rac1-ced-10-is-essential-in-maintaining-dopaminergic-neuron-function-and-survival-against-%C3%AE-synuclein-induced-toxicity
#9
Hanna Kim, Carles Calatayud, Sangib Guha, Irene Fernández-Carasa, Laura Berkowitz, Iria Carballo-Carbajal, Mario Ezquerra, Rubén Fernández-Santiago, Pankaj Kapahi, Ángel Raya, Antonio Miranda-Vizuete, Jose Miguel Lizcano, Miquel Vila, Kim A Caldwell, Guy A Caldwell, Antonella Consiglio, Esther Dalfo
Parkinson's disease is associated with intracellular α-synuclein accumulation and ventral midbrain dopaminergic neuronal death in the Substantia Nigra of brain patients. The Rho GTPase pathway, mainly linking surface receptors to the organization of the actin and microtubule cytoskeletons, has been suggested to participate to Parkinson's disease pathogenesis. Nevertheless, its exact contribution remains obscure. To unveil the participation of the Rho GTPase family to the molecular pathogenesis of Parkinson's disease, we first used C elegans to demonstrate the role of the small GTPase RAC1 (ced-10 in the worm) in maintaining dopaminergic function and survival in the presence of alpha-synuclein...
February 10, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29418023/a-noble-pathological-role-for-alpha-synuclein-in-triggering-neurodegeneration-of-parkinson-s-disease
#10
Alireza Bahiraee, Reyhane Ebrahimi
No abstract text is available yet for this article.
February 8, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29417441/glycotoxins-dietary-and-metabolic-origins-possible-amelioration-of-neurotoxicity-by-carnosine-with-special-reference-to-parkinson-s-disease
#11
REVIEW
Alan R Hipkiss
There is a strong association between neurodegeneration and protein glycation; possible origins of neurotoxic glycated protein, also called glycotoxins, include (i) diet (i.e., proteins cooked at high temperatures), (ii) protein glycation in the gut, and (iii) intracellular reaction of proteins with deleterious aldehydes, especially methylglyoxal (MG). It is likely that excessive glycolysis provokes increased generation of dihydroxyacetone phosphate which decomposes into MG due to activity-induced deamidation of certain asparagine residues in the glycolytic enzyme triose-phosphate isomerase (TPI)...
February 7, 2018: Neurotoxicity Research
https://www.readbyqxmd.com/read/29416594/pink1-suppresses-alpha-synuclein-induced-neuronal-injury-a-novel-mechanism-in-protein-phosphatase-2a-activation
#12
Weiwei Yang, Xue Wang, Jia Liu, Chunli Duan, Ge Gao, Lingling Lu, Shun Yu, Hui Yang
Alpha-synuclein (α-Syn) and phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced putative kinase (PINK) 1 are proteins found in Lewy bodies, which are a pathological hallmark of Parkinson's disease (PD). PINK1 overexpression suppresses α-Syn-induced phenotypes and increases lifespan and health in an animal model of PD. It has been suggested that the two proteins regulate protein phosphatase (PP) 2A activity, but the underlying mechanisms and neuroprotective action of PP2A against PD-associated pathology are unknown...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29414104/acrolein-mediated-neuronal-cell-death-and-alpha-synuclein-aggregation-implications-for-parkinson-s-disease
#13
Abeje Ambaw, Lingxing Zheng, Mitali A Tambe, Katherine E Strathearn, Glen Acosta, Scott A Hubers, Fang Liu, Seth A Herr, Jonathan Tang, Alan Truong, Elwood Walls, Amber Pond, Jean-Christophe Rochet, Riyi Shi
Growing evidence suggests that oxidative stress plays a critical role in neuronal destruction characteristic of Parkinson's disease (PD). However, the molecular mechanisms of oxidative stress-mediated dopaminergic cell death are far from clear. In the current investigation, we tested the hypothesis that acrolein, an oxidative stress and lipid peroxidation (LPO) product, is a key factor in the pathogenesis of PD. Using a combination of in vitro, in vivo, and cell free models, coupled with anatomical, functional, and behavioral examination, we found that acrolein was elevated in 6-OHDA-injected rats, and behavioral deficits associated with 6-OHDA could be mitigated by the application of the acrolein scavenger hydralazine, and mimicked by injection of acrolein in healthy rats...
January 29, 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29414102/drp-1-dependent-mitochondrial-fragmentation-and-protective-autophagy-in-dopaminergic-sh-sy5y-cells-overexpressing-alpha-synuclein
#14
Jimena Hebe Martinez, Agustina Alaimo, Roxana Mayra Gorojod, Soledad Porte Alcon, Federico Fuentes, Federico Coluccio Leskow, Mónica Lidia Kotler
Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibition of autophagy both events associated to the intracellular accumulation of α-synuclein. The mechanism by which these events contribute to neural degeneration remains unknown...
January 27, 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29411106/release-and-uptake-of-pathologic-alpha-synuclein
#15
REVIEW
Veselin Grozdanov, Karin M Danzer
Parkinson's disease (PD) is a chronic progressive neurodegenerative disease, which is characterized by severe loss of dopaminergic neurons and formation of Lewy bodies, which are rich in aggregated alpha-synuclein (α-syn). Two decades of intensive research have compiled a massive body of evidence that aggregation of α-syn is a critical process in PD and other synucleinopathies. The dissemination of Lewy body pathology throughout the central nervous system strongly suggests a cell-to-cell transmission of α-syn...
February 6, 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29409956/the-interaction-between-calcineurin-and-%C3%AE-synuclein-is-regulated-by-calcium-and-calmodulin
#16
Xiaoyu Shi, Yue Sun, Ping Wang, Lingling Gu, Lu Wang, Huan Yang, Qun Wei, Zhimei Li, Jing Luo
Calcineurin (CN) is a protein phosphatase and widely distributed in eukaryotes, with an extremely high level of expression in mammalian brain. Alpha-synuclein (α-syn) is a small soluble protein expressed primarily at presynaptic terminals in the central nervous system. In our present study, we explored the interactions between CN and α-syn in vitro. Based on the data from microscale thermophoresis, GST pull-down assays, and co-immunoprecipitation, we found that CN binds α-syn. Furthermore, this interaction is mediated by calcium/calmodulin (Ca2+/CaM) signaling...
January 30, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29408361/binding-of-alpha-synuclein-to-partially-oxidized-glyceraldehyde-3-phosphate-dehydrogenase-induces-subsequent-inactivation-of-the-enzyme
#17
Kseniya Barinova, Evgeniya Khomyakova, Pavel Semenyuk, Elena Schmalhausen, Vladimir Muronetz
According to literature data, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) co-localizes with alpha-synuclein in Lewy bodies in Parkinson's disease, which suggests the involvement of this protein in the development of synucleinopathies. The goal of the present work was to investigate the direct interaction between alpha-synuclein and GAPDH and to evaluate possible influence of this interaction on the catalytic properties of GAPDH. Molecular dynamic simulations predicted the binding of alpha-synuclein to the positively charged groove comprising NAD+-binding pocket of GAPDH...
February 3, 2018: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29407413/exacerbation-of-sensorimotor-dysfunction-in-mice-deficient-in-atp13a2-and-overexpressing-human-wildtype-alpha-synuclein
#18
Emily R Dirr, Osunde R Ekhator, Rachel Blackwood, John G Holden, Eliezer Masliah, Patrick J Schultheis, Sheila M Fleming
Loss of function mutations in the gene ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis, the former designated as an inherited form of Parkinson's disease (PD). The function of ATP13A2 is unclear but in vitro studies indicate it is a lysosomal protein and may interact with the presynaptic protein alpha-synuclein (aSyn) and certain heavy metals. Accumulation of aSyn is a major component of lewy bodies, the pathological hallmark of PD. Atp13a2-deficient (13a2) mice develop age-dependent sensorimotor deficits, and accumulation of insoluble aSyn in the brain...
January 31, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/29400668/best-practices-for-generating-and-using-alpha-synuclein-pre-formed-fibrils-to-model-parkinson-s-disease-in-rodents
#19
Nicole K Polinski, Laura A Volpicelli-Daley, Caryl E Sortwell, Kelvin C Luk, Nunilo Cremades, Lindsey M Gottler, Jessica Froula, Megan F Duffy, Virginia M Lee, Terina N Martinez, Kuldip D Dave
Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting approximately one-percent of the population over the age of sixty. Although many animal models have been developed to study this disease, each model presents its own advantages and caveats. A unique new model has arisen to study the role of alpha-synuclein (aSyn) in the pathogenesis of PD. This model involves the conversion of recombinant monomeric aSyn protein to a fibrillar form-the aSyn pre-formed fibril (aSyn PFF)-which is then injected into the brain or introduced to the media in culture...
January 30, 2018: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/29400127/glucocerebrosidase-and-parkinson-disease-molecular-clinical-and-therapeutic-implications
#20
Roberta Balestrino, Anthony H V Schapira
Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset...
February 1, 2018: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
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