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Alpha-synuclein

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https://www.readbyqxmd.com/read/29676021/detection-of-alpha-synuclein-conformational-variants-from-gastro-intestinal-biopsy-tissue-as-a-potential-biomarker-for-parkinson-s-disease
#1
Claudio Ruffmann, Nora Bengoa-Vergniory, Ilaria Poggiolini, Diane Ritchie, Michele T Hu, Javier Alegre-Abarrategui, Laura Parkkinen
AIMS: Gastrointestinal (GI) α-synuclein (aSyn) detection as a potential biomarker of Parkinson's disease (PD) is challenged by conflicting results of recent studies. To increase sensitivity and specificity, we applied three techniques to detect different conformations of aSyn in GI biopsies obtained from a longitudinal, clinically well-characterized cohort of PD patients and healthy controls (HC). METHODS: With immunohistochemistry (IHC), we used antibodies reactive for total, phosphorylated and oligomeric aSyn; with aSyn proximity ligation assay (AS-PLA), we targeted oligomeric aSyn species specifically; and with paraffin-embedded tissue blot (AS-PET-blot) we aimed to detect fibrillary, synaptic aSyn...
April 19, 2018: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29673913/epothilone-d-inhibits-microglia-mediated-spread-of-alpha-synuclein-aggregates
#2
Dario Valdinocci, Gary Grant, Tracey Dickson, Dean L Pountney
Multiple System Atrophy (MSA) is a progressive neurodegenerative disease characterized by chronic neuroinflammation and widespread α-synuclein (α-syn) cytoplasmic inclusions. Neuroinflammation associated with microglial cells is typically located in brain regions with α-syn deposits. The potential link between microglial cell migration and the transport of pathological α-syn protein in MSA was investigated. Qualitative analysis via immunofluorescence of MSA cases (n = 4) revealed microglial cells bearing α-syn inclusions distal from oligodendrocytes bearing α-syn cytoplasmic inclusions, as well as close interactions between microglia and oligodendrocytes bearing α-syn, suggestive of a potential transfer mechanism between microglia and α-syn bearing cells in MSA and the possibility of microglia acting as a mobile vehicle to spread α-syn between anatomically connected brain regions...
April 16, 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29669468/inducible-alpha-synuclein-expression-affects-human-neural-stem-cell-behavior
#3
Jacopo Zasso, Ahmed Mastad, Alessandro Cutarelli, Luciano Conti
Converging evidence suggest that levels of alpha-Synuclein (aSyn) expression play a critical role in Parkinson's disease (PD). Several mutations of the SNCA gene, encoding for aSyn have been associated to either the familial or the sporadic forms of PD. Nonetheless, the mechanism underlying wild type aSyn-mediated neurotoxicity in neuronal cells as well as its specific driving role in PD pathogenesis has yet to be fully clarified. In this view, the development of proper in vitro cellular systems is a crucial step...
April 19, 2018: Stem Cells and Development
https://www.readbyqxmd.com/read/29663556/structure-and-dynamics-of-the-extended-helix-state-of-alpha-synuclein-intrinsic-lability-of-the-linker-region
#4
Yoon-Hui Sung, David Eliezer
The Parkinson's protein alpha-synuclein binds to synaptic vesicles in vivo and adopts a highly extended helical conformation when binding to lipid vesicles in vitro. High-resolution structural analysis of alpha-synuclein bound to small lipid or detergent micelles revealed two helices connected by a non-helical linker, but corresponding studies of the vesicle-bound extended-helix state are hampered by the size and heterogeneity of the protein-vesicle complex. Here we employ fluorinated alcohols (FAs) to induce a highly helical aggregation-resistant state of alpha-synuclein in solution that resembles the vesicle-bound extended-helix state but is amenable to characterization using high-resolution solution-state NMR...
April 16, 2018: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/29662651/p27-kip1-regulates-alpha-synuclein-expression
#5
Edurne Gallastegui, Carla Domuro, Joan Serratosa, Alejandra Larrieux, Laura Sin, Jonatan Martinez, Arnaud Besson, José Manuel Morante-Redolat, Serena Orlando, Rosa Aligue, Isabel Fariñas, María Jesús Pujol, Oriol Bachs
Alpha-synuclein (α-SYN) is the main component of anomalous protein aggregates (Lewy bodies) that play a crucial role in several neurodegenerative diseases (synucleinopathies) like Parkinson's disease and multiple system atrophy. However, the mechanisms involved in its transcriptional regulation are poorly understood. We investigated here the role of the cyclin-dependent kinase (Cdk) inhibitor and transcriptional regulator p27Kip1 (p27) in the regulation of α-SYN expression. We observed that selective deletion of p27 by CRISPR/Cas9 technology in neural cells resulted in increased levels of α-SYN...
March 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29662465/the-length-of-snca-rep1-microsatellite-may-influence-cognitive-evolution-in-parkinson-s-disease
#6
Lucia Corrado, Fabiola De Marchi, Sara Tunesi, Gaia Donata Oggioni, Miryam Carecchio, Luca Magistrelli, Silvana Tesei, Giulio Riboldazzi, Alessio Di Fonzo, Clarissa Locci, Ilaria Trezzi, Roberta Zangaglia, Cristina Cereda, Sandra D'Alfonso, Corrado Magnani, Giacomo P Comi, Giorgio Bono, Claudio Pacchetti, Roberto Cantello, Stefano Goldwurm, Cristoforo Comi
Background: Alpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson's disease (PD). A previous study showed that a variant of the alpha-synuclein gene ( SNCA ), namely the 263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients...
2018: Frontiers in Neurology
https://www.readbyqxmd.com/read/29655942/pink1-p-k520rfsx3-mutation-identified-in-a-chinese-family-with-early-onset-parkinson-s-disease
#7
Peng Wang, Yi Guo, Chengyuan Song, Yiming Liu, Hao Deng
Parkinson's disease (PD) features selective loss of dopaminergic neurons of the substantia nigra pars compacta accompanied by the accumulation and aggregation of alpha-synuclein in Lewy bodies. PTEN induced putative kinase 1 gene (PINK1) mutations are the second most common genetic cause of autosomal recessive early-onset Parkinson's disease (EOPD). A single nucleotide deletion in PINK1 exon 8 (c.1557delG) was identified in a consanguineous Chinese family with EOPD. The homozygous deletion was co-segregated with disease in the family and resulted in a frameshift after codon 520 with a premature termination at codon 522 (p...
April 12, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29649746/degradation-of-alpha-synuclein-by-dendritic-cell-factor-1-delays-neurodegeneration-and-extends-lifespan-in-drosophila
#8
Shiqing Zhang, Ruili Feng, Yanhui Li, Linhua Gan, Fangfang Zhou, Shiquan Meng, Qian Li, Tieqiao Wen
Parkinson's disease (PD) is a common neurodegenerative disease associated with the progressive loss of dopaminergic neurons in the substantia nigra. Proteinaceous depositions of alpha-synuclein (α-syn) and its mutations, A30P and A53T, are one important characteristic of PD. However, little is known about their aggregation and degradation mechanisms. Dendritic cell factor 1 (DCF1) is a membrane protein that plays important roles in nerve development in mouse. In this study, we aimed to show that DCF1 overexpression in a PD Drosophila model significantly ameliorates impaired locomotor behavior in third instar larvae and normalizes neuromuscular junction growth...
March 13, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29625255/genetic-enhancement-of-macroautophagy-in-vertebrate-models-of-neurodegenerative-diseases
#9
REVIEW
Patrick Ejlerskov, Avraham Ashkenazi, David C Rubinsztein
Most of the neurodegenerative diseases that afflict humans manifest with the intraneuronal accumulation of toxic proteins which are aggregate-prone. Extensive data in cell and neuronal models support the concept that such proteins, like mutant huntingtin or alpha-synuclein, are substrates for macroautophagy (hereafter autophagy). Furthermore, autophagy-inducing compounds lower the levels of such proteins and ameliorate their toxicity in diverse animal models of neurodegenerative diseases. However, most of these compounds also have autophagy-independent effects and it is important to understand if similar benefits are seen with genetic strategies that upregulate autophagy, as this strengthens the validity of this strategy in such disease...
April 3, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29624752/biomarkers-for-cognitive-impairment-in-lewy-body-disorders-status-and-relevance-for-clinical-trials
#10
REVIEW
Andrew Siderowf, Dag Aarsland, Brit Mollenhauer, Jennifer G Goldman, Bernard Ravina
Biomarkers have the potential to improve diagnosis and prognosis, and guide clinical treatment decisions. In research, biomarkers can be used for patient selection and as outcome measures in clinical trials. A range of biochemical and imaging biomarkers are relevant to patients with Lewy body disorders, including PD, PD dementia, and dementia with Lewy bodies. Dopaminergic imaging is used for differential diagnosis of parkinsonian disorders versus tremor disorders without dopamingeric deficits, and also to differentiate dementia with Lewy bodies from Alzheimer's disease...
April 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29624735/cx3cr1-deficiency-exacerbates-alpha-synuclein-a53t-induced-neuroinflammation-and-neurodegeneration-in-a-mouse-model-of-parkinson-s-disease
#11
Sara Castro-Sánchez, Ángel J García-Yagüe, Tresa López-Royo, Maria Casarejos, José Luis Lanciego, Isabel Lastres-Becker
Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons of the substantia nigra and the accumulation of protein aggregates, called Lewy bodies, where the most abundant is alpha-synuclein (α-SYN). Mutations of the gene that codes for α-SYN (SNCA), such as the A53T mutation, and duplications of the gene generate cases of PD with autosomal dominant inheritance. As a result of the association of inflammation with the neurodegeneration of PD, we analyzed whether overexpression of wild-type α-SYN (α-SYNWT ) or mutated α-SYN (α-SYNA53T ) are involved in the neuronal dopaminergic loss and inflammation process, along with the role of the chemokine fractalkine (CX3CL1) and its receptor (CX3CR1)...
April 6, 2018: Glia
https://www.readbyqxmd.com/read/29623065/-in-situ-proximity-ligation-assay-reveals-co-localization-of-alpha-synuclein-and-snare-proteins-in-murine-primary-neurons
#12
Leire Almandoz-Gil, Emma Persson, Veronica Lindström, Martin Ingelsson, Anna Erlandsson, Joakim Bergström
The aggregation of alpha-synuclein (αSyn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of αSyn is to promote the soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between αSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA)...
2018: Frontiers in Neurology
https://www.readbyqxmd.com/read/29615762/small-molecules-attenuate-the-interplay-between-conformational-fluctuations-early-oligomerization-and-amyloidosis-of-alpha-synuclein
#13
Sumanta Ghosh, Amrita Kundu, Krishnananda Chattopadhyay
Aggregation of alpha synuclein has strong implications in Parkinson's disease. The heterogeneity of folding/aggregation landscape and transient nature of the early intermediates result in difficulty in developing a successful therapeutic intervention. Here we used fluorescence measurements at ensemble and single molecule resolution to study how the late and early events of alpha synuclein aggregation modulate each other. In-vitro aggregation data was complemented using measurements inside live neuroblastoma cells by employing a small molecule labeling technique...
April 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29608598/sequestration-of-synaptic-proteins-by-alpha-synuclein-aggregates-leading-to-neurotoxicity-is-inhibited-by-small-peptide
#14
Mal-Gi Choi, Mi Jin Kim, Do-Geun Kim, Ri Yu, You-Na Jang, Won-Jong Oh
α-Synuclein (α-syn) is a major component of Lewy bodies found in synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Under the pathological conditions, α-syn tends to generate a diverse form of aggregates showing toxicity to neuronal cells and able to transmit across cells. However, mechanisms by which α-syn aggregates affect cytotoxicity in neurons have not been fully elucidated. Here we report that α-syn aggregates preferentially sequester specific synaptic proteins such as vesicle-associated membrane protein 2 (VAMP2) and synaptosomal-associated protein 25 (SNAP25) through direct binding which is resistant to SDS...
2018: PloS One
https://www.readbyqxmd.com/read/29604467/decreased-expression-of-serum-and-glucocorticoid-inducible-kinase-1-sgk1-promotes-alpha-synuclein-increase-related-with-down-regulation-of-dopaminergic-cell-in-the-substantia-nigra-of-chronic-mptp-induced-parkinsonism-mice-and-in-sh-sy5y-cells
#15
Sujung Yeo, Backil Sung, Yeon-Mi Hong, Maurits van den Noort, Peggy Bosch, Sook-Hyun Lee, Jongbeom Song, Sang-Kyun Park, Sabina Lim
Parkinson's disease (PD) is a chronically progressive neurodegenerative disease, with its main pathological hallmarks being a dramatic loss of dopaminergic neurons predominantly in the Substantia Nigra (SN), and the formations of intracytoplasmic Lewy bodies and dystrophic neurites. Alpha-synuclein (α-syn), widely recognized as the most prominent element of the Lewy body, is one of the representative hallmarks in PD. However, the mechanisms behind the increased α-syn expression and aggregation have not yet been clarified...
March 28, 2018: Gene
https://www.readbyqxmd.com/read/29604408/evaluation-of-fgf-20-variants-for-susceptibility-to-parkinson-s-disease-in-eastern-indians
#16
Dipanwita Sadhukhan, Gautami Das, Arindam Biswas, Soumitra Ghosh, Shyamal K Das, Kunal Ray, Jharna Ray
BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease and has a complex etiology. Single nucleotide polymorphisms in the 3'-untranslated region of Fibroblast growth factor 20 (FGF 20) have been reported to be associated with PD; however, the results are controversial. Although FGF20 enhances the survival of dopaminergic neurons, it may also result in PD susceptibility by altering alpha-synuclein expression. MATERIALS AND METHODS: To identify and characterize genetic risk variants in FGF 20 in Eastern Indian PD patients, 2 SNPs of FGF 20 (rs1721100 and rs2720208) were genotyped in 336 PD cases and 313 ethnically matched controls by PCR-RFLP...
March 28, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29601177/pulsed-hdx-illuminates-the-aggregation-kinetics-of-alpha-synuclein-the-causative-agent-for-parkinson-s-disease
#17
Eva Illes-Toth, Don L Rempel, Michael L Gross
Alpha-synuclein (aS) forms toxic intermediates ranging from small oligomers and protofibrils to large amyloid fibrils. Understanding the time course of aS fibril formation and the role played by its regions is critical for therapeutic intervention. Here, we used pulsed hydrogen-deuterium-exchange and mass spectrometry (HDX-MS) for the first time to probe kinetic intermediates of the full aS aggregation in vitro, achieving kinetic snapshots containing spatially resolved protein information about critical stages...
March 30, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29600388/alpha-synuclein-is-present-in-dental-calculus-but-not-altered-in-parkinson-s-disease-patients-in-comparison-to-controls
#18
Sabrina Schmid, Eva Goldberg-Bockhorn, Silke Schwarz, Nicole Rotter, Jan Kassubek, Kelly Del Tredici, Elmar Pinkhardt, Markus Otto, Albert C Ludolph, Patrick Oeckl
INTRODUCTION: In autopsy cases staged for sporadic Parkinson's disease (PD), the neuropathology is characterized by a preclinical phase that targets the enteric nervous system of the gastrointestinal tract (GIT). Therefore, the ENS might be a source of potential (presymptomatic) PD biomarkers. METHODS: In this clinically based study, we examined the alpha-synuclein (αSyn) concentration in an easily accessible protein storage medium of the GIT, dental calculus, in 21/50 patients with PD and 28/50 age- and gender-matched controls using ELISA...
March 29, 2018: Journal of Neurology
https://www.readbyqxmd.com/read/29599149/alpha-synuclein-aggregates-activate-calcium-pump-serca-leading-to-calcium-dysregulation
#19
Cristine Betzer, Louise Berkhoudt Lassen, Anders Olsen, Rikke Hahn Kofoed, Lasse Reimer, Emil Gregersen, Jin Zheng, Tito Calì, Wei-Ping Gai, Tong Chen, Arne Moeller, Marisa Brini, Yuhong Fu, Glenda Halliday, Tomasz Brudek, Susana Aznar, Bente Pakkenberg, Jens Peter Andersen, Poul Henning Jensen
Aggregation of α-synuclein is a hallmark of Parkinson's disease and dementia with Lewy bodies. We here investigate the relationship between cytosolic Ca2+ and α-synuclein aggregation. Analyses of cell lines and primary culture models of α-synuclein cytopathology reveal an early phase with reduced cytosolic Ca2+ levels followed by a later Ca2+ increase. Aggregated but not monomeric α-synuclein binds to and activates SERCA in vitro , and proximity ligation assays confirm this interaction in cells. The SERCA inhibitor cyclopiazonic acid (CPA) normalises both the initial reduction and the later increase in cytosolic Ca2+ CPA protects the cells against α-synuclein-aggregate stress and improves viability in cell models and in Caenorhabditis elegans in vivo Proximity ligation assays also reveal an increased interaction between α-synuclein aggregates and SERCA in human brains affected by dementia with Lewy bodies...
March 29, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29595653/type-i-gaucher-disease-with-bullous-pemphigoid-and-parkinson-disease-a-case-report
#20
Damien Le Peillet, Virginie Prendki, Véronique Trombert, Emmanuel Laffitte, Frédéric Assal, Jean Luc Reny, Christine Serratrice
RATIONALE: Gaucher disease (GD) is a rare genetic lysosomal storage disorder inherited in an autosomal recessive pattern. GD is due to the deficiency of a lysosomal enzyme, acid beta-glucosidase (or glucocerebrosidase). Type 1 Gaucher disease (GD1) is characterized by thrombocytopenia, anemia, an enlarged spleen, and liver as well as bone complications (Erlenmeyer flask deformity, osteoporosis, lytic lesions, pathological and vertebral fractures, bone infarcts, and avascular necrosis leading to degenerative arthropathy)...
March 2018: Medicine (Baltimore)
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