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synuclein and aggregation

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https://www.readbyqxmd.com/read/27904575/alpha-synuclein-structure-functions-and-interactions
#1
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/27901101/structural-basis-for-the-dissociation-of-%C3%AE-synuclein-fibrils-triggered-by-pressure-perturbation-of-the-hydrophobic-core
#2
Guilherme A P de Oliveira, Mayra de A Marques, Carolina Cruzeiro-Silva, Yraima Cordeiro, Caroline Schuabb, Adolfo H Moraes, Roland Winter, Hartmut Oschkinat, Debora Foguel, Mônica S Freitas, Jerson L Silva
Parkinson's disease is a neurological disease in which aggregated forms of the α-synuclein (α-syn) protein are found. We used high hydrostatic pressure (HHP) coupled with NMR spectroscopy to study the dissociation of α-syn fibril into monomers and evaluate their structural and dynamic properties. Different dynamic properties in the non-amyloid-β component (NAC), which constitutes the Greek-key hydrophobic core, and in the acidic C-terminal region of the protein were identified by HHP NMR spectroscopy. In addition, solid-state NMR revealed subtle differences in the HHP-disturbed fibril core, providing clues to how these species contribute to seeding α-syn aggregation...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27901068/nanomechanical-properties-of-distinct-fibrillar-polymorphs-of-the-protein-%C3%AE-synuclein
#3
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
#4
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
#5
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/27892477/nanomolar-oligomerization-and-selective-co-aggregation-of-%C3%AE-synuclein-pathogenic-mutants-revealed-by-single-molecule-fluorescence
#6
Emma Sierecki, Nichole Giles, Quill Bowden, Mark E Polinkovsky, Janina Steinbeck, Nicholas Arrioti, Diya Rahman, Akshay Bhumkar, Philip R Nicovich, Ian Ross, Robert G Parton, Till Böcking, Yann Gambin
Protein aggregation is a hallmark of many neurodegenerative diseases, notably Alzheimer's and Parkinson's disease. Parkinson's disease is characterized by the presence of Lewy bodies, abnormal aggregates mainly composed of α-synuclein. Moreover, cases of familial Parkinson's disease have been linked to mutations in α-synuclein. In this study, we compared the behavior of wild-type (WT) α-synuclein and five of its pathological mutants (A30P, E46K, H50Q, G51D and A53T). To this end, single-molecule fluorescence detection was coupled to cell-free protein expression to measure precisely the oligomerization of proteins without purification, denaturation or labelling steps...
November 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27875637/ambra1-a-novel-%C3%AE-synuclein-binding-protein-is-implicated-in-the-pathogenesis-of-multiple-system-atrophy
#7
Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Yota Tatara, Jun Utsumi, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Gian Maria Fimia, Koichi Wakabayashi
The accumulation of abnormal α-synuclein is the major histopathological feature of Lewy body disease and multiple system atrophy (MSA), which are referred to as synucleinopathies. Although the pathomechanisms underlying synucleinopathies are still unknown, mounting evidence indicates that cytoplasmic degradation systems, such as the autophagy-lysosome and proteasome pathways, are strongly involved in their pathogenesis. Autophagy is tightly regulated by several upstream proteins including UNC-51-like kinase 1/2, beclin1, vacuolar protein sorting-associated protein 34, and autophagy/beclin1 regulator 1 (AMBRA1)...
November 22, 2016: Brain Pathology
https://www.readbyqxmd.com/read/27866262/impairment-of-mitochondria-dynamics-by-human-a53t-%C3%AE-synuclein-and-rescue-by-nap-davunetide-in-a-cell-model-for-parkinson-s-disease
#8
T Q Melo, K C van Zomeren, M F R Ferrari, H W G M Boddeke, J C V M Copray
The formation of oligomers and aggregates of overexpressed or mutant α-synuclein play a role in the degeneration of dopaminergic neurons in Parkinson's disease by causing dysfunction of mitochondria, reflected in their disturbed mobility and production of ROS. The mode of action and mechanisms underlying this mitochondrial impairment is still unclear. We have induced stable expression of wild-type, A30P or A53T α-synuclein in neuronally differentiated SH-SY5Y neuroblastoma cells and studied anterograde and retrograde mitochondrial trafficking in this cell model for Parkinson's disease...
November 19, 2016: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
https://www.readbyqxmd.com/read/27865997/homogentisic-acid-induces-aggregation-and-fibrillation-of-amyloidogenic-proteins
#9
Daniela Braconi, Lia Millucci, Andrea Bernini, Ottavia Spiga, Pietro Lupetti, Barbara Marzocchi, Neri Niccolai, Giulia Bernardini, Annalisa Santucci
BACKGROUND: Alkaptonuria (AKU) is an ultra-rare inborn error of metabolism characterized by homogentisic acid (HGA) accumulation due to a deficient activity of the homogentisate 1.2-dioxygenase (HGD) enzyme. This leads to the production of dark pigments that are deposited onto connective tissues, a condition named 'ochronosis' and whose mechanisms are not completely clear. Recently, the potential role of hitherto unidentified proteins in the ochronotic process was hypothesized, and the presence of Serum Amyloid A (SAA) in alkaptonuric tissues was reported, allowing the classification of AKU as a novel secondary amyloidosis...
November 16, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27863716/antibodies-against-the-c-terminus-of-%C3%AE-synuclein-modulate-its-fibrillation
#10
Cagla Sahin, Nikolai Lorenzen, Lasse Lemminger, Gunna Christiansen, Ian Max Møller, Louise Buur Vesterager, Lars Østergaard Pedersen, Karina Fog, Pekka Kallunki, Daniel E Otzen
The 140-residue natively disordered protein α-synuclein (aSN) is a central component in the development of a family of neurodegenerative diseases termed synucleinopathies. This is attributed to its ability to form cytotoxic aggregates such as oligomers and amyloid fibrils. Consequently there have been intense efforts to avoid aggregation or reroute the aggregation pathway using pharmaceutical agents such as small molecules, chaperones and antibodies. aSN's lack of persistent structure in the monomeric state, as well as the multitude of different oligomeric and even different fibrillar states, makes it difficult to raise antibodies that would be efficacious in neutralizing all conformations of aSN...
January 2017: Biophysical Chemistry
https://www.readbyqxmd.com/read/27862428/an-iridium-iii-complex-as-a-photoactivatable-tool-for-oxidation-of-amyloidogenic-peptides-with-subsequent-modulation-of-peptide-aggregation
#11
Juhye Kang, Shin Jung C Lee, Jung Seung Nam, Hyuck Jin Lee, Myeong-Gyun Kang, Kyle J Korshavn, Hyun-Tak Kim, Jaeheung Cho, Ayyalusamy Ramamoorthy, Hyun-Woo Rhee, Tae-Hyuk Kwon, Mi Hee Lim
Aggregates of amyloidogenic peptides are involved in the pathogenesis of several degenerative disorders. Herein, we report an Ir(III) complex, Ir-1, as a chemical tool for oxidizing amyloidogenic peptides upon photoactivation and subsequently modulating their aggregation pathways. Ir-1 was rationally designed based on multiple characteristics, including (i) photoproperties leading to excitation by low-energy radiation; (ii) generation of reactive oxygen species responsible for peptide oxidation upon photoactivation under mild conditions; (iii) relatively easy incorporation of a ligand on the Ir(III) center for specific interactions with amyloidogenic peptides...
November 15, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27860405/flow-cytometric-screening-of-aggregation-inhibitors-using-a-fluorescence-assisted-intracellular-method
#12
Hanna Lindberg, Lisa Sandersjöö, Sebastian W Meister, Mathias Uhlén, John Löfblom, Stefan Ståhl
Aggregation of misfolded peptides and proteins is a key event in several neurodegenerative diseases. Suggested treatments of such disorders aim to inhibit the initial aggregation process. Here, we have developed an intracellular, function-based screening method, intended for isolation of aggregation-inhibitors from combinatorial protein libraries by flow-cytometric cell sorting. The method is based on fusion of aggregation-prone peptides to a fluorescent protein, functioning as a solubility reporter. Co-expression of a protein-based aggregation-inhibitor should prevent aggregation and thus increase the whole-cell fluorescence...
November 17, 2016: Biotechnology Journal
https://www.readbyqxmd.com/read/27853754/commentary-alpha-synuclein-interacts-with-sod1-and-promotes-its-oligomerization
#13
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
#14
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/27852849/robust-cns-pathology-in-transgenic-mice-following-peripheral-injection-of-%C3%AE-synuclein-fibrils
#15
Jacob I Ayers, Mieu M Brooks, Nicola J Rutherford, Jasie K Howard, Zachary A Sorrentino, Cara J Riffe, Benoit I Giasson
: Misfolded α-synuclein (αS) is hypothesized to spread throughout the CNS by neuronal connectivity leading to widespread pathology. Increasing evidence indicates that it also has the potential to invade the CNS via peripheral nerves in a prion-like manner. Based on the effectiveness following peripheral routes of prion administration, we extend our previous studies of CNS neuroinvasion in M83 αS transgenic mice following hindlimb muscle (IM) injection of αS fibrils by comparing various peripheral sites of inoculations with different αS protein preparations...
November 16, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27837450/subcellular-parkinson-s-disease-specific-alpha-synuclein-species-show-altered-behavior-in-neurodegeneration
#16
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/27829983/melatoninergic-system-in-parkinson-s-disease-from-neuroprotection-to-the-management-of-motor-and-nonmotor-symptoms
#17
REVIEW
Josiel Mileno Mack, Marissa Giovanna Schamne, Tuane Bazanella Sampaio, Renata Aparecida Nedel Pértile, Pedro Augusto Carlos Magno Fernandes, Regina P Markus, Rui Daniel Prediger
Melatonin is synthesized by several tissues besides the pineal gland, and beyond its regulatory effects in light-dark cycle, melatonin is a hormone with neuroprotective, anti-inflammatory, and antioxidant properties. Melatonin acts as a free-radical scavenger, reducing reactive species and improving mitochondrial homeostasis. Melatonin also regulates the expression of neurotrophins that are involved in the survival of dopaminergic neurons and reduces α-synuclein aggregation, thus protecting the dopaminergic system against damage...
2016: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/27826641/synucleinopathies-common-features-and-hippocampal-manifestations
#18
REVIEW
Weiwei Yang, Shun Yu
Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA) are three major synucleinopathies characterized by α-synuclein-containing inclusions in the brains of patients. Because the cell types and brain structures that are affected vary markedly between the disorders, the patients have different clinical manifestations in addition to some overlapping symptoms, which are the basis for differential diagnosis. Cognitive impairment and depression associated with hippocampal dysfunction are frequently observed in these disorders...
November 8, 2016: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/27826104/in-vivo-and-in-silico-studies-to-identify-mechanisms-associated-with-nurr1-modulation-following-early-life-exposure-to-permethrin-in-rats
#19
Donatella Fedeli, Maura Montani, Laura Bordoni, Roberta Galeazzi, Cinzia Nasuti, Luísa Correia-Sá, Valentina F Domingues, Maini Jayant, Vani Brahmachari, Luca Massaccesi, Emiliano Laudadio, Rosita Gabbianelli
The present work was designed to study the mechanisms associated with Nurr1 modulation following early life permethrin (PERM) treatment during rat's life span. Here we demonstrate that PERM exposure in rats, at a dose close to No Observed Adverse Effect Level (NOAEL) for 15days during neonatal brain development leads to its accumulation long after exposure. In striatum from adolescent rats we detected an increase in DNA methyltransferases (DNMTs) such as DNMT1, DNMT3a, Tyrosine hydroxylase, monomeric and aggregated α-synuclein protein levels...
November 5, 2016: Neuroscience
https://www.readbyqxmd.com/read/27824888/bifunctional-anti-non-amyloid-component-%C3%AE-synuclein-nanobodies-are-protective-in-situ
#20
David C Butler, Shubhada N Joshi, Erwin De Genst, Ankit S Baghel, Christopher M Dobson, Anne Messer
Misfolding, abnormal accumulation, and secretion of α-Synuclein (α-Syn) are closely associated with synucleinopathies, including Parkinson's disease (PD). VH14 is a human single domain intrabody selected against the non-amyloid component (NAC) hydrophobic interaction region of α-Syn, which is critical for initial aggregation. Using neuronal cell lines, we show that as a bifunctional nanobody fused to a proteasome targeting signal, VH14PEST can counteract heterologous proteostatic effects of mutant α-Syn on mutant huntingtin Exon1 and protect against α-Syn toxicity using propidium iodide or Annexin V readouts...
2016: PloS One
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