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synuclein and aggregation

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https://www.readbyqxmd.com/read/28811225/alpha-synuclein-ferrireductase-activity-is-detectible-in-vivo-is-altered-in-parkinson-s-disease-and-increases-the-neurotoxicity-of-dopal
#1
Jennifer S McDowall, Ioanna Ntai, Kevin C Honeychurch, John P Hart, Philippe Colin, Bernard L Schneider, David R Brown
The normal cellular role of α-synuclein is of potential importance in understanding diseases in which an aggregated form of the protein has been implicated. A potential loss or change in the normal function of α-synuclein could play a role in the aetiology of diseases such as Parkinson's disease. Recently, it has been suggested that α-synuclein could cause the enzymatic reduction of iron and a cellular increase in Fe(II) levels. Experiments were carried out to determine if such activity could be determined in vivo...
August 12, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28810585/glutamine-promotes-hsp70-and-inhibits-%C3%AE-synuclein-accumulation-in-pheochromocytoma-pc12-cells
#2
Haiyang Wang, Chongyang Tang, Zhenfeng Jiang, Xiao Zhou, Jianhang Chen, Meng Na, Hong Shen, Zhiguo Lin
Hsp70 regulates α-Synuclein (α-Syn) degeneration in Parkinson's disease (PD), indicating that Hsp70 promotion may be able to prevent or reverse α-Syn-induced toxicity in PD. Additionally, it has been demonstrated that glutamine (Gln) enhances Hsp70 expression. In the present study, Gln-induced Hsp70 promotion in pheochromocytoma was investigated with reverse transcription- quantitative polymerase chain reaction and western blotting methods. Then it was observed whether heat shock factor (HSF)-1 was required for this phenomenon with an RNA interference strategy...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28808780/non-cns-pathogenic-origin-of-parkinson-s-disease
#3
Humdoon Choudhry, Lawrence C Perlmuter
The gut with its variety of microbiota may serve as an etiological origin of diseases. Gut microbes may also play a role in the pathogenesis of diseases beyond their simple nutritional maintenance and support. For example, gut protein aggregation, possibly aided by microbes as well as nasal influences, might be linked to disease that may move to the brain through the vagus nerve. To this end, Braak has offered a "dual-hit" hypothesis that proposes a novel etiology for Parkinson's disease (PD). The hypothesis places the initial origin of the disease in the nose and the gastrointestinal tract (GI) after infection by an unknown pathogen that could aggregate in the gut and then eventually spread to the brain via the autonomic plexuses...
August 14, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28804999/diversity-of-astroglial-responses-across-human-neurodegenerative-disorders-and-brain-aging
#4
Isidro Ferrer
Astrogliopathy refers to alterations of astrocytes occurring in diseases of the nervous system, and it implies the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Reactive astrocytosis refers to the response of astrocytes to different insults to the nervous system, whereas astrocytopathy indicates hypertrophy, atrophy/degeneration and loss of function and pathological remodeling occurring as a primary cause of a disease or as a factor contributing to the development and progression of a particular disease...
September 2017: Brain Pathology
https://www.readbyqxmd.com/read/28803148/combustion-derived-nanoparticles-the-neuroenteric-system-cervical-vagus-hyperphosphorylated-alpha-synuclein-and-tau-in-young-mexico-city-residents
#5
Lilian Calderón-Garcidueñas, Rafael Reynoso-Robles, Beatriz Pérez-Guillé, Partha S Mukherjee, Angélica Gónzalez-Maciel
Mexico City (MC) young residents are exposed to high levels of fine particulate matter (PM2.5), have high frontal concentrations of combustion-derived nanoparticles (CDNPs), accumulation of hyperphosphorylated aggregated α-synuclein (α-Syn) and early Parkinson's disease (PD). Swallowed CDNPs have easy access to epithelium and submucosa, damaging gastrointestinal (GI) barrier integrity and accessing the enteric nervous system (ENS). This study is focused on the ENS, vagus nerves and GI barrier in young MC v clean air controls...
August 9, 2017: Environmental Research
https://www.readbyqxmd.com/read/28801354/following-the-fate-of-endocytosed-fibrils
#6
Masato Hasegawa, Genjiro Suzuki
Cell-to-cell transmission of intracellular protein aggregates is considered a central event in many neurodegenerative diseases, but little is known about the underlying molecular mechanisms. A new study employs fluorescence quenching to examine the fate of α-synuclein, a key molecule in the pathology of Parkinson's disease and related disorders, in primary cultured neurons, finding that endocytosis and lysosomal processing of exogenous fibrils may explain the transmission of α-synuclein pathology.
August 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28797124/preclinical-development-of-a-vaccine-against-oligomeric-alpha-synuclein-based-on-virus-like-particles
#7
Marika Doucet, Aadil El-Turabi, Franziska Zabel, Benjamin H M Hunn, Nora Bengoa-Vergniory, Milena Cioroch, Mauricio Ramm, Amy M Smith, Ariane Cruz Gomes, Gustavo Cabral de Miranda, Richard Wade-Martins, Martin F Bachmann
Parkinson's disease (PD) is a progressive and currently incurable neurological disorder characterised by the loss of midbrain dopaminergic neurons and the accumulation of aggregated alpha-synuclein (a-syn). Oligomeric a-syn is proposed to play a central role in spreading protein aggregation in the brain with associated cellular toxicity contributing to a progressive neurological decline. For this reason, a-syn oligomers have attracted interest as therapeutic targets for neurodegenerative conditions such as PD and other alpha-synucleinopathies...
2017: PloS One
https://www.readbyqxmd.com/read/28797122/cross-seeding-of-prions-by-aggregated-%C3%AE-synuclein-leads-to-transmissible-spongiform-encephalopathy
#8
Elizaveta Katorcha, Natallia Makarava, Young Jin Lee, Iris Lindberg, Mervyn J Monteiro, Gabor G Kovacs, Ilia V Baskakov
Aggregation of misfolded proteins or peptides is a common feature of neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, prion and other diseases. Recent years have witnessed a growing number of reports of overlap in neuropathological features that were once thought to be unique to only one neurodegenerative disorder. However, the origin for the overlap remains unclear. One possibility is that diseases with mixed brain pathologies might arise from cross-seeding of one amyloidogenic protein by aggregated states of unrelated proteins...
August 10, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28796507/molecular-dynamics-study-to-investigate-the-dimeric-structure-of-the-full-length-%C3%AE-synuclein-in-aqueous-solution
#9
Tingting Zhang, Yuanxin Tian, Zhonghuang Li, Siming Liu, Xiang Hu, Zichao Yang, Xiaotong Ling, Shu-Wen Liu, Jiajie Zhang
The mechanisms of dimerization of α-Synuclein from full-length monomers and the structural features have been investigated through molecular dynamics simulations in this study. The dimerization of α-Syn plays a critical role in the fibrillogenesis mechanism and could initiate and trigger α-Syn to aggregate by conformational transforming. According to the alignment between three regions of α-Syn monomer, 8 diverse starting structures have been constructed. However, only 5 configurations show the dimeric structures and the detailed properties of 3 dimers of them are discussed...
August 10, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28794461/non-uniform-self-assembly-on-the-anisotropic-architecture-of-%C3%AE-synuclein-supra-fibrillar-aggregates
#10
Slav A Semerdzhiev, Volodymyr V Shvadchak, Vinod Subramaniam, Mireille M A E Claessens
Although the function of biopolymer hydrogels in nature depends on structural anisotropy at mesoscopic length scales, the self-assembly of such anisotropic structures in vitro is challenging. Here we show that fibrils of the protein α-synuclein spontaneously self-assemble into structurally anisotropic hydrogel particles. While the fibrils in the interior of these supra-fibrillar aggregates (SFAs) are randomly oriented, the fibrils in the periphery prefer to cross neighboring fibrils at high angles. This difference in organization coincides with a significant difference in polarity of the environment in the central and peripheral parts of the SFA...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28794446/impaired-endo-lysosomal-membrane-integrity-accelerates-the-seeding-progression-of-%C3%AE-synuclein-aggregates
#11
Peizhou Jiang, Ming Gan, Shu-Hui Yen, Pamela J McLean, Dennis W Dickson
In neurodegenerative diseases, seeding is a process initiated by the internalization of exogenous protein aggregates. Multiple pathways for internalization of aggregates have been proposed, including direct membrane penetration and endocytosis. To decipher the seeding mechanisms of alpha-synuclein (αS) aggregates in human cells, we visualized αS aggregation, endo-lysosome distribution, and endo-lysosome rupture in real-time. Our data suggest that exogenous αS can seed endogenous cytoplasmic αS by either directly penetrating the plasma membrane or via endocytosis-mediated endo-lysosome rupture, leading to formation of endo-lysosome-free or endo-lysosome-associated αS aggregates, respectively...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28792609/egcg-attenuates-fe-iii-induced-conformational-transition-of-%C3%AE-synuclein-and-protects-as-pc12-cells-against-fe-iii-induced-death
#12
Juan Zhao, Lihui Xu, Qingnan Liang, Qing Sun, Congheng Chen, Yuan Zhang, Yu Ding, Ping Zhou
The fibrillation and aggregation of α-synuclein (AS), along with the conformational transition from random coil to β-sheet, are the critical steps in the development of Parkinson's disease (PD). It is acknowledged that iron accumulation in the brain may lead to the fibrillation of AS. However, (-)-epigallocatechin gallate (EGCG) can penetrate the blood-brain barrier, chelate metal ions and inhibit the fibrillation of amyloid proteins. Therefore, EGCG is warranted to be investigated for its potential to cure amyloid-related diseases...
August 9, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28790323/mitochondrial-division-inhibitor-1-is-neuroprotective-in-the-a53t-%C3%AE-synuclein-rat-model-of-parkinson-s-disease
#13
Simone Bido, Federico N Soria, Rebecca Z Fan, Erwan Bezard, Kim Tieu
Alpha-synuclein (α-syn) is involved in both familial and sporadic Parkinson's disease (PD). One of the proposed pathogenic mechanisms of α-syn mutations is mitochondrial dysfunction. However, it is not entirely clear the impact of impaired mitochondrial dynamics induced by α-syn on neurodegeneration and whether targeting this pathway has therapeutic potential. In this study we evaluated whether inhibition of mitochondrial fission is neuroprotective against α-syn overexpression in vivo. To accomplish this goal, we overexpressed human A53T-α- synuclein (hA53T-α-syn) in the rat nigrostriatal pathway, with or without treatment using the small molecule Mitochondrial Division Inhibitor-1 (mdivi-1), a putative inhibitor of the mitochondrial fission Dynamin-Related Protein-1 (Drp1)...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28790319/novel-animal-model-defines-genetic-contributions-for-neuron-to-neuron-transfer-of-%C3%AE-synuclein
#14
Trevor Tyson, Megan Senchuk, Jason F Cooper, Sonia George, Jeremy M Van Raamsdonk, Patrik Brundin
Cell-to-cell spreading of misfolded α-synuclein (α-syn) is suggested to contribute to the progression of neuropathology in Parkinson's disease (PD). Compelling evidence supports the hypothesis that misfolded α-syn transmits from neuron-to-neuron and seeds aggregation of the protein in the recipient cells. Furthermore, α-syn frequently appears to propagate in the brains of PD patients following a stereotypic pattern consistent with progressive spreading along anatomical pathways. We have generated a C. elegans model that mirrors this progression and allows us to monitor α-syn neuron-to-neuron transmission in a live animal over its lifespan...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28780180/neuropathology-of-parkinson-disease
#15
Dennis W Dickson
INTRODUCTION: Parkinson's disease (PD) is characterized by bradykinesia, rigidity, postural instability and tremor. Several pathologic processes can produce this syndrome, but neurodegeneration accompanied by neuronal inclusions composed of α-synuclein (Lewy bodies) is considered the typical pathologic correlate of PD. METHODS: The neuropathologic features of PD are reviewed based upon personal experience and review of the literature. Molecular pathology of PD is summarized from cell biological and animal studies...
August 1, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28780169/the-pmr1-pump-in-alpha-synuclein-toxicity-and-neurodegeneration
#16
REVIEW
Vassiliki Nikoletopoulou, Nektarios Tavernarakis
Proteinopathies constitute a diverse group of devastating neurodegenerative disorders, characterized by aberrant aggregation of specific proteins within neurons and in the brain parenchyma. Parkinson's disease (PD) is among the most common proteinopathies, caused by the accumulation of different species of α-synuclein and the formation of protein inclusions known as Lewy bodies. Although several mutations in the α-synuclein gene have been linked to PD, the mechanisms mediating the aggregation and toxicity of α-synuclein are not fully understood...
August 2, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28771510/quantitative-proteomics-in-a30p-a53t-%C3%AE-synuclein-transgenic-mice-reveals-upregulation-of-sel1l
#17
Jianguo Yan, Pei Zhang, Fengjuan Jiao, Qingzhi Wang, Feng He, Qian Zhang, Zheng Zhang, Zexi Lv, Xiang Peng, Hongwei Cai, Bo Tian
α-Synuclein is an abundantly expressed neuronal protein that is at the center of focus in understanding a group of neurodegenerative disorders called synucleinopathies, which are characterized by the intracellular presence of aggregated α-synuclein. However, the mechanism of α-synuclein biology in synucleinopathies pathogenesis is not fully understood. In this study, mice overexpressing human A30P*A53T α-synuclein were evaluated by a motor behavior test and count of TH-positive neurons, and then two-dimensional liquid chromatography-tandem mass spectrometry coupled with tandem mass tags (TMTs) labeling was employed to quantitatively identify the differentially expressed proteins of substantia nigra pars compacta (SNpc) tissue samples that were obtained from the α-synuclein transgenic mice and wild type controls...
2017: PloS One
https://www.readbyqxmd.com/read/28770651/multiple-system-atrophy-many-lessons-from-the-transcriptome
#18
Ashton Curry-Hyde, Bei Jun Chen, Uwe Ueberham, Thomas Arendt, Michael Janitz
Multiple system atrophy (MSA) is a complex, multifactorial, debilitating neurodegenerative disease that is often misdiagnosed and misunderstood. MSA has two subclasses, MSA-P and MSA-C, defined by the dominance of parkinsonism or cerebellar dysfunction in the earlier stages of disease, coupled with dysautonomia. This distinction between subclasses becomes largely redundant as the disease progresses. Aggregation of α-synuclein is a clinical marker used to confirm MSA diagnoses, which can only be performed postmortem...
August 1, 2017: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
https://www.readbyqxmd.com/read/28767194/echinacoside-s-nigrostriatal-dopaminergic-protection-against-6-ohda-induced-endoplasmic-reticulum-stress-through-reducing-the-accumulation-of-seipin
#19
Yajie Zhang, Hongyan Long, Fuqiong Zhou, Weina Zhu, Jie Ruan, Yang Zhao, Yan Lu
Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent epidemiological studies suggest that echinacoside (ECH), a phenylethanoid glycoside found in Cistanche deserticola, has a protective effect against the development of PD. However, the detailed mechanisms of how ECH suppresses neuronal death have not been fully elucidated. In this study, we confirmed that ECH protects nigrostriatal neurons against 6-hydroxydopamine (6-OHDA)-induced endoplasmic reticulum stress (ERS) in vivo and in vitro...
August 2, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28763613/the-importance-of-mitophagy-in-maintaining-mitochondrial-function-in-u373mg-cells-bafilomycin-a1-restores-aminochrome-induced-mitochondrial-damage
#20
Sandro Huenchuguala, Patricia Muñoz, Juan Segura-Aguilar
Aminochrome, an orthoquinone formed during the dopamine oxidation of neuromelanin, is neurotoxic because it induces mitochondria dysfunction, protein degradation dysfunction (both autophagy and proteasomal systems), α-synuclein aggregation to neurotoxic oligomers, neuroinflammation, and oxidative and endoplasmic reticulum stress. In this study, we investigated the relationship between aminochrome-induced autophagy/lysosome dysfunction and mitochondrial dysfunction in U373MGsiGST6 cells. Aminochrome (75 μM) induces mitochondrial dysfunction as determined by (i) a significant decrease in ATP levels (70%; P < 0...
August 15, 2017: ACS Chemical Neuroscience
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