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Alpha synuclein

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https://www.readbyqxmd.com/read/28719185/small-molecule-enhancement-of-20s-proteasome-activity-targets-intrinsically-disordered-proteins
#1
Corey L Jones, Evert Njomen, Benita Sjogren, Thomas S Dexheimer, Jetze J Tepe
The 20S proteasome is the main protease for degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceed proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disor-ders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity...
July 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28711409/nortriptyline-inhibits-aggregation-and-neurotoxicity-of-alpha-synuclein-by-enhancing-reconfiguration-of-the-monomeric-form
#2
Timothy J Collier, Kinshuk R Srivastava, Craig Justman, Tom Grammatopoulous, Birgit Hutter-Paier, Manuela Prokesch, Daniel Havas, Jean-Christophe Rochet, Fang Liu, Kevin Jock, Patrícia de Oliveira, Georgia L Stirtz, Ulf Dettmer, Caryl E Sortwell, Mel B Feany, Peter Lansbury, Lisa Lapidus, Katrina L Paumier
The pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar α-synuclein (α-syn). One strategy to slow disease progression is to prevent the misfolding and aggregation of its native monomeric form. Here we present findings that support the contention that the tricyclic antidepressant compound nortriptyline (NOR) has disease-modifying potential for synucleinopathies. Findings from in vitro aggregation and kinetics assays support the view that NOR inhibits aggregation of α-syn by directly binding to the soluble, monomeric form, and by enhancing reconfiguration of the monomer, inhibits formation of toxic conformations of the protein...
July 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28710275/a-ph-dependent-switch-promotes-%C3%AE-synuclein-fibril-formation-via-glutamate-residues
#3
Gina M Moriarty, Michael P Olson, Tamr B Atieh, Maria K Janowska, Sagar D Khare, Jean Baum
Alpha-synuclein (αS) is the primary protein associated with Parkinson's disease, and undergoes aggregation from its intrinsically disordered monomeric form to a cross-β fibrillar form. The closely related homolog beta-synuclein (βS) is essentially fibril resistant under cytoplasmic physiological conditions. Toxic gain of function by βS has been linked to dysfunction, but the aggregation behavior of βS under altered pH is not well understood. In this work, we compare fibril formation of αS and βS at pH 7...
July 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28707886/diarylheptanoids-from-rhizomes-of-alpinia-officinarum-inhibit-aggregation-of-alpha-synuclein
#4
Guangmiao Fu, Wei Zhang, Dongsheng Du, Yu Pong Ng, Fanny C F Ip, Rongbiao Tong, Nancy Y Ip
Two new diarylheptanoids, alpinins A (1) and B (2), together with eighteen known diarylheptanoids (3-20), were isolated from the rhizomes of Alpinia officinarum. Their structures were elucidated by comprehensive spectroscopic analysis including HRMS, IR, and 1D- and 2D-NMR. Structurally, alpinin A is a new member of the small family of oxa-bridged diarylheptanoids and contains the characteristic 2,6-cis-configured tetrahydropyran motif (C1-C5 oxa-bridge). The absolute configuration of alpinin A was confirmed by asymmetric total synthesis of the enantiomer (ent-1), corroborating the assignment of the molecular structure...
July 14, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28702523/implications-of-peptide-assemblies-in-amyloid-diseases
#5
REVIEW
Pu Chun Ke, Marc-Antonie Sani, Feng Ding, Aleksandr Kakinen, Ibrahim Javed, Frances Separovic, Thomas P Davis, Raffaele Mezzenga
Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology - much of which are poorly understood - these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer's, Parkinson's, type 2 diabetes and prion diseases...
July 12, 2017: Chemical Society Reviews
https://www.readbyqxmd.com/read/28696461/room-temperature-in-cell-epr-spectroscopy-alpha-synuclein-disease-variants-remain-intrinsically-disordered-in-the-cell
#6
Julia Cattani, Vinod Subramaniam, Malte Drescher
Human alpha-Synuclein (aS), implicated in Parkinson's disease, adopts a rich variety of different conformations depending on the macromolecular context. In order to unravel its pathophysiological role, monitoring its intracellular conformational state and identifying differences for the disease variants is crucial. Here, we present an intracellular spectroscopy approach based on a systematic spin-labeling site-scan in combination with intracellular electron paramagnetic resonance spectroscopy determining conformations on a molecular scale...
July 11, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28690195/low-molar-excess-of-4-oxo-2-nonenal-and-4-hydroxy-2-nonenal-promote-oligomerization-of-alpha-synuclein-through-different-pathways
#7
Leire Almandoz-Gil, Hedvig Welander, Elisabet Ihse, Payam Emami Khoonsari, Sravani Musunuri, Christofer Lendel, Jessica Sigvardson, Mikael Karlsson, Martin Ingelsson, Kim Kultima, Joakim Bergström
Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7...
July 6, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28677385/minimal-nucleation-state-of-%C3%AE-synuclein-is-stabilized-by-dynamic-threonine-water-networks
#8
Tod D Romo, Andrew K Lewis, Anthony R Braun, Alan Grossfield, Jonathan N Sachs
The first structures of α-synuclein (αSyn) fibrils have recently been solved. Here, we use a unique combination of molecular dynamics simulation strategies to address the minimal nucleation size of the 11-amino acid NAC protofibril solved by X-ray and to interrogate the dynamic behavior of unexpected crystal waters in the steric zipper. We found that protofibrils of >8 chains are thermodynamically stabilized due to protection of the fibril core from solvent influx and ordering of the end strands by the fibril core...
July 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28676755/variants-in-snca-gene-are-associated-with-parkinson-s-disease-risk-and-cognitive-symptoms-in-a-brazilian-sample
#9
Clarissa L C Campêlo, Fernanda C Cagni, Diego de Siqueira Figueredo, Luiz G Oliveira, Antônio B Silva-Neto, Priscila T Macêdo, José R Santos, Geison S Izídio, Alessandra M Ribeiro, Tiago G de Andrade, Clécio de Oliveira Godeiro, Regina H Silva
Genetic susceptibility contributes to the etiology of sporadic Parkinson's Disease (PD) and worldwide studies have found positive associations of polymorphisms in the alpha-synuclein gene (SNCA) with the risk for PD. However, little is known about the influence of variants of SNCA in individual traits or phenotypical aspects of PD. Further, there is a lack of studies with Latin-American samples. We evaluated the association between SNCA single nucleotide polymorphisms (single nucleotide polymorphisms, SNPs - rs2583988, rs356219, rs2736990, and rs11931074) and PD risk in a Brazilians sample...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28676095/toll-like-receptor-4-stimulation-with-monophosphoryl-lipid-a-ameliorates-motor-deficits-and-nigral-neurodegeneration-triggered-by-extraneuronal-%C3%AE-synucleinopathy
#10
Serena Venezia, Violetta Refolo, Alexia Polissidis, Leonidas Stefanis, Gregor K Wenning, Nadia Stefanova
BACKGROUND: Alpha-synuclein (α-syn) aggregation represents the pathological hallmark of α-synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Toll-like receptors (TLRs) are a family of highly conserved molecules that recognize pathogen-associated molecular patterns and define the innate immunity response. It was previously shown that TLR4 plays a role in the clearance of α-syn, suggesting that TLR4 up-regulation in microglia may be a natural mechanism to improve the clearance of α-syn...
July 4, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28666710/homozygous-alpha-synuclein-p-a53v-in-familial-parkinson-s-disease
#11
Hiroyo Yoshino, Makito Hirano, A Jon Stoessl, Yoko Imamichi, Aya Ikeda, Yuanzhe Li, Manabu Funayama, Ikuko Yamada, Yusaku Nakamura, Vesna Sossi, Matthew J Farrer, Kenya Nishioka, Nobutaka Hattori
We have assessed the frequency of alpha-synuclein (SNCA) mutations in Japanese patients with familial or sporadic Parkinson's disease (PD) and surveyed their associated clinical manifestations. We screened SNCA exon 3 in 988 patients without SNCA multiplications (430 with autosomal dominant PD and 558 with sporadic PD). We detected 1 patient harboring a homozygous SNCA p.A53V substitution albeit with an autosomal dominant pattern of disease inheritance (frequency 2/860 = 0.2%). The proband manifested slow and progressive parkinsonism at 55 years...
June 27, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28659169/the-novel-compound-pbt434-prevents-iron-mediated-neurodegeneration-and-alpha-synuclein-toxicity-in-multiple-models-of-parkinson-s-disease
#12
David I Finkelstein, Jessica L Billings, Paul A Adlard, Scott Ayton, Amelia Sedjahtera, Colin L Masters, Simon Wilkins, David M Shackleford, Susan A Charman, Wojciech Bal, Izabela A Zawisza, Ewa Kurowska, Andrew L Gundlach, Sheri Ma, Ashley I Bush, Dominic J Hare, Philip A Doble, Simon Crawford, Elisabeth Cl Gautier, Jack Parsons, Penny Huggins, Kevin J Barnham, Robert A Cherny
Elevated iron in the SNpc may play a key role in Parkinson's disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions...
June 28, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28656548/treadmill-exercise-attenuates-%C3%AE-synuclein-levels-by-promoting-mitochondrial-function-and-autophagy-possibly-via-sirt1-in-the-chronic-mptp-p-induced-mouse-model-of-parkinson-s-disease
#13
Jung-Hoon Koo, Joon-Yong Cho
Accumulation of alpha-synuclein (α-Syn) is significantly correlated with the presence of progressive motor deficits, which is the main symptom of Parkinson's disease (PD). Although physical exercise reduces α-Syn levels, the molecular mechanisms by which physical exercise decreases α-Syn remain unclear. We hypothesized that treadmill exercise (TE) decreases α-Syn levels by improving mitochondrial function and promoting autophagy via the sirtuin-1 (SIRT1) signaling pathway in the chronic 1-methyl-1,2,3,6-tetrahydropyridine with probenecid (MPTP/P)-induced mouse model of PD...
June 27, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28653979/hypermethylation-of-synphilin-1-alpha-synuclein-interacting-protein-sncaip-gene-in-the-cerebral-cortex-of-patients-with-sporadic-parkinson-s-disease
#14
Khashayar Dashtipour, Ali Tafreshi, Charles Adler, Thomas Beach, Xin Chen, Geidy Serrano, Stephanie Tashiro, Charles Wang
OBJECTIVE: To determine and compare DNA methylation patterns between patients with Parkinson's disease (PD) and age- and sex-similar matched non-PD controls. BACKGROUND: Epigenetic regulation is one of the major mechanisms for an organism to respond to the environment through changes in gene expression and has been implicated in numerous disease processes. We would like to examine epigenetic modification patterns that may predispose or protect against PD. METHODS: Frozen tissue samples of the human cerebral cortex from 12 PD patients and 12 subjects without PD pathology were obtained...
June 27, 2017: Brain Sciences
https://www.readbyqxmd.com/read/28651250/a-role-for-neuronal-alpha-synuclein-in-gastrointestinal-immunity
#15
Ethan Stolzenberg, Deborah Berry, De Yang, Ernest Y Lee, Alexander Kroemer, Stuart Kaufman, Gerard C L Wong, Joost J Oppenheim, Supti Sen, Thomas Fishbein, Ad Bax, Brent Harris, Denise Barbut, Michael A Zasloff
BACKGROUND: Alpha-synuclein (αS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of αS within the enteric nervous system (ENS) and its traffic from the gut to the brain are implicated in the pathogenesis and progression of PD. αS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked αS to immune cell activation in the central nervous system. We hypothesized that αS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract...
June 27, 2017: Journal of Innate Immunity
https://www.readbyqxmd.com/read/28647363/cadps2-gene-expression-is-oppositely-regulated-by-lrrk2-and-alpha-synuclein
#16
Julia Obergasteiger, Christa Überbacher, Peter P Pramstaller, Andrew A Hicks, Corrado Corti, Mattia Volta
The Ca(2+)-dependent activator protein for secretion 2 (CADPS2) is a member of the CAPS/CADPS protein family that plays crucial roles in synaptic vesicle dynamics. Genomic variability in the CADPS2 gene has been associated to autism spectrum disorders and Alzheimer's disease, both characterized by altered neurotransmission. Biological evidence also linked CADPS2 to Parkinson's disease (PD), as a disease-causing mutation in leucine-rich repeat kinase 2 (LRRK2) was reported to increase CADPS2 gene and protein expression...
June 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28645308/neonatal-aav-delivery-of-alpha-synuclein-induces-pathology-in-the-adult-mouse-brain
#17
Marion Delenclos, Ayman H Faroqi, Mei Yue, Aishe Kurti, Monica Castanedes-Casey, Linda Rousseau, Virginia Phillips, Dennis W Dickson, John D Fryer, Pamela J McLean
Abnormal accumulation of alpha-synuclein (αsyn) is a pathological hallmark of Lewy body related disorders such as Parkinson's disease and Dementia with Lewy body disease. During the past two decades, a myriad of animal models have been developed to mimic pathological features of synucleinopathies by over-expressing human αsyn. Although different strategies have been used, most models have little or no reliable and predictive phenotype. Novel animal models are a valuable tool for understanding neuronal pathology and to facilitate development of new therapeutics for these diseases...
June 23, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28642128/immunomodulation-of-parkinson-s-disease-using-mucuna-pruriens-mp
#18
REVIEW
Sachchida Nand Rai, Hareram Birla, Walia Zahra, Saumitra Sen Singh, Surya Pratap Singh
Immune control is associated with nigrostriatal neuroprotection for Parkinson's disease (PD); though its direct cause and effect relationships have not yet been realized and modulating the immune system for therapeutic gain has been openly discussed. While the pathobiology of PD remains in study, neuroinflammation is thought to speed nigrostriatal degeneration. The neuroinflammatory cascade associated with PD begins with aggregation of misfolded or post-translationally modified α-synuclein (α-syn). Such aggregation results in neuronal cell death and the presence of chronically activated glia (microglia and astroglia), leading to the production of proinflammatory cytokines like tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and cyclooxygenase-2 (COX-2)...
June 19, 2017: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/28631520/striatal-changes-underlie-mpep-mediated-suppression-of-the-acquisition-and-expression-of-pramipexole-induced-place-preference-in-an-alpha-synuclein-rat-model-of-parkinson-s-disease
#19
Simon Loiodice, Portia McGhan, Vitalina Gryshkova, Renaud Fleurance, David Dardou, Aziz Hafidi, Andre Nogueira da Costa, Franck Durif
Impulsive-compulsive disorders in Parkinson's disease patients have been described as behavioural or substance addictions including pathological gambling or compulsive medication use of dopamine replacement therapy. A substantial gap remains in the understanding of these disorders. We previously demonstrated that the rewarding effect of the D2/D3 agonist pramipexole was enhanced after repeated exposure to L-dopa and alpha-synuclein mediated dopaminergic nigral loss with specific transcriptional signatures suggesting a key involvement of the glutamatergic pathway...
June 1, 2017: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/28623611/deferiprone-rescues-behavioral-deficits-induced-by-mild-iron-exposure-in-a-mouse-model-of-alpha-synuclein-aggregation
#20
Eleonora Carboni, Lars Tatenhorst, Lars Tönges, Elisabeth Barski, Vivian Dambeck, Mathias Bähr, Paul Lingor
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and its causes remain unknown. A major hallmark of the disease is the increasing presence of aggregated alpha-synuclein (aSyn). Furthermore, there is a solid consensus on iron (Fe) accumulation in several regions of PD brains during disease progression. In our study, we focused on the interaction of Fe and aggregating aSyn in vivo in a transgenic mouse model overexpressing human aSyn bearing the A53T mutation (prnp.aSyn.A53T). We utilized a neonatal iron-feeding model to exacerbate the motor phenotype of the transgenic mouse model...
June 16, 2017: Neuromolecular Medicine
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