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Alpha-synuclein

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https://www.readbyqxmd.com/read/28425704/an-ortho-iminoquinone-compound-reacts-with-lysine-inhibiting-aggregation-while-remodeling-mature-amyloid-fibrils
#1
Luiza Fernandes, Nathália Moraes, Fernanda Savacini Sagrillo, Augusto V Magalhães, Marcela Cristina de Moraes, Luciana Romão, Jeffery W Kelly, Debora Foguel, Neil P Grimster, Fernando L Palhano
Protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. It has been shown that lysine residues play a key role in the formation of these aggregates. Thus the ability to disrupt aggregate formation by covalently modifying lysine residues could lead to the discovery of therapeutically relevant anti-amyloidogenesis compounds. Herein, we demonstrate that an ortho-iminoquinone (IQ) can be utilized to inhibit amyloid aggregation. Using alpha-synuclein and Aβ1-40 as model systems, we observed that IQ was able to react with lysine residues and reduce amyloid aggregation...
April 20, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28424577/investigation-of-endocytic-pathways-for-the-internalization-of-exosome-associated-oligomeric-alpha-synuclein
#2
Marion Delenclos, Teodora Trendafilova, Divya Mahesh, Ann M Baine, Simon Moussaud, Irene K Yan, Tushar Patel, Pamela J McLean
Misfolding and aggregation of alpha-synuclein (αsyn) resulting in cytotoxicity is a hallmark of Parkinson's disease (PD) and related synucleinopathies. The recent body of evidence indicates that αsyn can be released from neuronal cells by nonconventional exocytosis involving extracellular vesicles (EVs) such as exosomes. The transfer of αsyn between cells has been proposed to be an important mechanism of disease propagation in PD. To date, exosome trafficking mechanisms, including release and cell-cell transmission, have not been fully described...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28420950/metallothionein-copper-and-alpha-synuclein-in-alpha-synucleinopathies
#3
REVIEW
Yuho Okita, Alexandre N Rcom-H'cheo-Gauthier, Michael Goulding, Roger S Chung, Peter Faller, Dean L Pountney
Metallothioneins (MTs) are proteins that function by metal exchange to regulate the bioavailability of metals, such as zinc and copper. Copper functions in the brain to regulate mitochondria, neurotransmitter production, and cell signaling. Inappropriate copper binding can result in loss of protein function and Cu(I)/(II) redox cycling can generate reactive oxygen species. Copper accumulates in the brain with aging and has been shown to bind alpha-synuclein and initiate its aggregation, the primary aetiological factor in Parkinson's disease (PD), and other alpha-synucleinopathies...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28419566/perirhinal-accumulation-of-neuronal-alpha-synuclein-in-a-multiple-system-atrophy-patient-with-dementia
#4
Mari Saito, Makoto Hara, Momoko Ebashi, Akihiko Morita, Kyoko Okada, Taku Homma, Masahiko Sugitani, Kentaro Endo, Toshiki Uchihara, Satoshi Kamei
We report the case of a 79-year-old Japanese woman who developed cerebellar ataxia followed by rigidity, dysautonomia and cognitive disorders, and was thus clinically diagnosed as having possible MSA with dementia. Neuropathological findings demonstrated not only olivopontocerebellar and striatonigral degeneration with frequent glial cytoplasmic inclusions (GCIs), but also degenerative changes in the parahippocampal region, accentuated in the anterior portion of perirhinal cortex, where neuronal cytoplasmic inclusions (NCIs) and NFTs were numerous while GCIs were limited...
April 16, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/28418693/validating-the-predicted-effect-of-astemizole-and-ketoconazole-using-a-drosophila-model-of-parkinson-s-disease
#5
Katarzyna Styczyńska-Soczka, Luigi Zechini, Lysimachos Zografos
Parkinson's disease is a growing threat to an ever-ageing population. Despite progress in our understanding of the molecular and cellular mechanisms underlying the disease, all therapeutics currently available only act to improve symptoms and do not stop the disease process. It is therefore imperative that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's. Drug repurposing has been recognized as being equally as promising as de novo drug discovery in the field of neurodegeneration and Parkinson's disease specifically...
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28417442/mechanisms-of-gene-environment-interactions-in-parkinson-s-disease
#6
REVIEW
Sheila M Fleming
PURPOSE OF REVIEW: The purpose of the study was to discuss the main mechanisms associated with environmental and genetic factors that contribute to the development of Parkinson's disease (PD). RECENT FINDINGS: Novel genetic contributors to PD are being identified at a rapid pace in addition to novel environmental factors. The discovery of mutations in alpha-synuclein and leucine-rich repeat kinase 2 causing inherited forms of PD along with epidemiological, in vitro, and in vivo studies identifying herbicides, pesticides, and metals as risk factors have dramatically improved our understanding of mechanisms involved in the development of PD...
April 17, 2017: Current Environmental Health Reports
https://www.readbyqxmd.com/read/28413000/derivation-of-mouse-embryonic-stem-cell-lines-from-tyrosine-hydroxylase-reporter-mice-crossed-with-a-human-snca-transgenic-mouse-model-of-parkinson-s-disease
#7
Margarita Chumarina, Carla Azevedo, Julie Bigarreau, Clémentine Vignon, Kwang-Soo Kim, Jia-Yi Li, Laurent Roybon
Mouse embryonic stem cell (mESC) lines were derived by crossing heterozygous transgenic (tg) mice expressing green fluorescent protein (GFP) under the control of the rat tyrosine hydroxylase (TH) promoter, with homozygous alpha-synuclein (aSYN) mice expressing human mutant SNCA(A53T) under the control of the mouse Prion promoter (MoPrP), or wildtype (WT) mice. The expression of GFP and human aSYN was validated by immunocytochemistry in midbrain neuron cultures upon differentiation of mESC lines using stromal cell-derived inducing activity...
March 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28409245/snca-3-utr-genetic-variants-in-patients-with-parkinson-s-disease-and-rem-sleep-behavior-disorder
#8
M Toffoli, E Dreussi, E Cecchin, M Valente, N Sanvilli, M Montico, S Gagno, M Garziera, M Polano, M Savarese, G Calandra-Buonaura, F Placidi, M Terzaghi, G Toffoli, G L Gigli
REM sleep behavior disorder (RBD) is an early marker of Parkinson's disease (PD); however, it is still unclear which patients with RBD will eventually develop PD. Single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of alpha-synuclein (SNCA) have been associated with PD, but at present, no data is available about RBD. The 3'UTR hosts regulatory regions involved in gene expression control, such as microRNA binding sites. The aim of this study was to determine RBD specific genetic features associated to an increased risk of progression to PD, by sequencing of the SNCA-3'UTR in patients with "idiopathic" RBD (iRBD) and in patients with PD...
April 13, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28400134/alpha-synuclein-pathology-mitochondrial-dysfunction-and-neuroinflammation-in-parkinson-s-disease
#9
REVIEW
Emily M Rocha, Briana De Miranda, Laurie H Sanders
Parkinson's disease (PD) is a complex, chronic and progressive neurodegenerative disease. While the etiology of PD is likely multifactorial, the protein α-synuclein is a central component to the pathogenesis of the disease. However, the mechanism by which α-synuclein causes toxicity and contributes to neuronal death remains unclear. Mitochondrial dysfunction is also widely considered to play a major role in the underlying mechanisms contributing to neurodegeneration in PD. This review discusses evidence for the neuropathological role for α-synuclein in the dysfunction of dopamine neurons in PD...
April 8, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28386933/novel-conformation-selective-alpha-synuclein-antibodies-raised-against-different-in-vitro-fibril-forms-show-distinct-patterns-of-lewy-pathology-in-parkinson-s-disease
#10
Dustin J Covell, John L Robinson, Rizwan S Akhtar, Murray Grossman, Daniel Weintraub, Hannah M Bucklin, Rose M Pitkin, Dawn Riddle, Ahmed Yousef, John Q Trojanowski, Virginia M-Y Lee
AIMS: The aim of this study was to test the hypothesis that different conformations of misfolded α-synuclein (α-syn) are present in Parkinson's disease (PD) brain. METHODS: Using two previously characterized conformations of α-syn fibrils, we generated new conformation-selective, α-syn monoclonal antibodies (mAbs). We then interrogated multiple brain regions in a well-characterized autopsy cohort of PD patients (n = 49) with these mAbs, Syn7015 and Syn9029. RESULTS: Syn7015 detects Lewy bodies (LBs) and Lewy neurites (LNs) formed by pathological α-syn in all brain regions tested, and is particularly sensitive to LNs and small Lewy dots, inclusions believed to form early in the disease...
April 7, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28379951/correction-the-mechanism-of-sirtuin-2-mediated-exacerbation-of-alpha-synuclein-toxicity-in-models-of-parkinson-disease
#11
Rita Machado de Oliveira, Hugo Vicente Miranda, Laetitia Francelle, Raquel Pinho, Éva M Szegö, Renato Martinho, Francesca Munari, Diana F Lázaro, Sébastien Moniot, Patrícia Guerreiro, Luis Fonseca-Ornelas, Zrinka Marijanovic, Pedro Antas, Ellen Gerhardt, Francisco Javier Enguita, Bruno Fauvet, Deborah Penque, Teresa Faria Pais, Qiang Tong, Stefan Becker, Sebastian Kügler, Hilal Ahmed Lashuel, Clemens Steegborn, Markus Zweckstetter, Tiago Fleming Outeiro
[This corrects the article DOI: 10.1371/journal.pbio.2000374.].
April 2017: PLoS Biology
https://www.readbyqxmd.com/read/28378233/multiple-system-atrophy-state-of-the-art
#12
REVIEW
Brice Laurens, Sylvain Vergnet, Miguel Cuina Lopez, Alexandra Foubert-Samier, François Tison, Pierre-Olivier Fernagut, Wassilios G Meissner
Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder that is characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. Some symptomatic treatments are available while neuroprotection or disease-modification remain unmet treatment needs. The pathologic hallmark is the accumulation of aggregated alpha-synuclein (α-syn) in oligodendrocytes forming glial cytoplasmic inclusions, which qualifies MSA as synucleinopathy together with Parkinson's disease and dementia with Lewy bodies...
May 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28374838/a-novel-tool-for-monitoring-endogenous-alpha-synuclein-transcription-by-nanoluciferase-tag-insertion-at-the-3-end-using-crispr-cas9-genome-editing-technique
#13
Sambuddha Basu, Levi Adams, Subhrangshu Guhathakurta, Yoon-Seong Kim
α-synuclein (α-SYN) is a major pathologic contributor to Parkinson's disease (PD). Multiplication of α-SYN encoding gene (SNCA) is correlated with early onset of the disease underlining the significance of its transcriptional regulation. Thus, monitoring endogenous transcription of SNCA is of utmost importance to understand PD pathology. We developed a stable cell line expressing α-SYN endogenously tagged with NanoLuc luciferase reporter using CRISPR/Cas9-mediated genome editing. This allows efficient measurement of transcriptional activity of α-SYN in its native epigenetic landscape which is not achievable using exogenous transfection-based luciferase reporter assays...
April 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28373279/a-sensitive-assay-reveals-structural-requirements-for-alpha-synuclein-fibril-growth
#14
Dhruva D Dhavale, Christina Tsai, Devika P Bagchi, Laura A Engel, Jonathan Sarezky, Paul T Kotzbauer
The accumulation of alpha-synuclein (α-syn) fibrils in neuronal inclusions is the defining pathological process in Parkinson disease (PD). A pathogenic role for α-syn fibril accumulation is supported by the identification of dominantly inherited α-syn (SNCA) gene mutations in rare cases of familial PD. Fibril formation involves a spontaneous nucleation event in which soluble α-syn monomers associate to form seeds, followed by fibril growth during which monomeric α-syn molecules sequentially associate with existing seeds...
April 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28370471/motor-deficits-and-beta-oscillations-are-dissociable-in-an-alpha-synuclein-model-of-parkinson-s-disease
#15
Ivani Brys, Jessica Nunes, Romulo Fuentes
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor symptoms resulting from chronic loss of dopaminergic neurons in the nigrostriatal pathway. The over expression of the protein alpha-synuclein in the substantia nigra has been used to induce progressive dopaminergic neuronal loss and to reproduce key histopathological and temporal features of PD in animal models. However the neurophysiological aspects of the alpha-synuclein PD model have been poorly characterized. Hereby we performed chronic in vivo electrophysiological recordings in the corticostriatal circuit of rats injected with viral vector to over express alpha-synuclein in the right substantia nigra...
March 30, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28369321/sodium-butyrate-rescues-dopaminergic-cells-from-alpha-synuclein-induced-transcriptional-deregulation-and-dna-damage
#16
Isabel Paiva, Raquel Pinho, Maria Angeliki S Pavlou, Magali Hennion, Pauline Wales, Anna-Lena Schütz, Ashish Rajput, Éva Szego, Cemil Kerimoglu, Ellen Gerhardt, Ana Cristina Rego, André Fischer, Stefan Bonn, Tiago F Outeiro
Alpha-synuclein (aSyn) is considered a major culprit in Parkinson's Disease (PD) pathophysiology. However, the precise molecular function of the protein remains elusive. Recent evidence suggests that aSyn may play a role on transcription regulation, possibly by modulating the acetylation status of histones. Our study aimed at evaluating the impact of wild-type (WT) and mutant A30P aSyn on gene expression, in a dopaminergic neuronal cell model, and decipher potential mechanisms underlying aSyn-mediated transcriptional deregulation...
March 24, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28362802/comparison-of-independent-screens-on-differentially-vulnerable-motor-neurons-reveals-alpha-synuclein-as-a-common-modifier-in-motor-neuron-diseases
#17
Rachel A Kline, Kevin A Kaifer, Erkan Y Osman, Francesco Carella, Ariana Tiberi, Jolill Ross, Giuseppa Pennetta, Christian L Lorson, Lyndsay M Murray
The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28361483/immunocytochemical-monitoring-of-pink1-parkin-mediated-mitophagy-in-cultured-cells
#18
Motoki Fujimaki, Shinji Saiki, Yukiko Sasazawa, Kei-Ichi Ishikawa, Yoko Imamichi, Katsuhiko Sumiyoshi, Nobutaka Hattori
Both PINK1 and parkin are the responsible genes (PARK6 and PARK2, respectively) for familial early-onset Parkinson's disease (PD). Several lines of evidences have suggested that mitochondrial dysfunction would be associated with PD pathogenesis. Lewy body, one of PD pathological hallmarks, contains alpha-synuclein, a familial PD (PARK1/4)-gene product, which is eliminated by macroautophagy, while PINK1 and parkin coordinately mediate mitophagy (hereafter called as PINK1/parkin-mediated mitophagy) reported firstly by Youle's group...
March 31, 2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28360124/genetic-mutations-linked-to-parkinson-s-disease-differentially-control-nucleolar-activity-in-pre-symptomatic-mouse-models
#19
V Evsyukov, A Domanskyi, H Bierhoff, S Gispert, R Mustafa, F Schlaudraff, B Liss, R Parlato
Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting nucleolar dysfunction as a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) modeling the multifactorial etiology of this disease.To this end, we analyzed a novel mouse model mildly overexpressing the mutant human-A53T-alpha-synuclein (hA53T-SNCA/PARK1) in a PTEN-induced kinase 1 (PINK1/PARK6) knock-out background and mutant mice lacking both DJ-1/PARK7 and PINK1/PARK6...
March 30, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28357149/festination-correlates-with-snca-polymorphism-in-chinese-patients-with-parkinson-s-disease
#20
Jinhua Zheng, Xinglong Yang, Quanzhen Zhao, Sijia Tian, Hongyan Huang, Yalan Chen, Yanming Xu
The genetic basis of festination, a common motor symptom in Parkinson's disease (PD), remains unclear. Since polymorphism in the alpha-synuclein (SNCA) gene is associated with PD phenotype, we examined whether such polymorphism is also associated with festination. SNCA polymorphisms rs11931074 and rs894278 were genotyped in a consecutive series of 258 patients with PD, of whom 122 (47.3%) suffered festination. Univariate analysis revealed significant differences in genotype and minor allele frequencies at rs11931074 or rs894278 between patients with festination and those without it (all p < 0...
2017: Parkinson's Disease
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