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Alpha synuclein

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https://www.readbyqxmd.com/read/28323023/internalization-axonal-transport-and-release-of-fibrillar-forms-of-alpha-synuclein
#1
Gregor Bieri, Aaron D Gitler, Michel Brahic
Intra-neuronal protein aggregates made of fibrillar alpha-synuclein (α-syn) are the hallmark of Parkinson's disease (PD). With time, these aggregates spread through the brain following axonal projections. Understanding the mechanism of this spread is central to the study of the progressive nature of PD. Here we review data relevant to the uptake, transport and release of α-syn fibrils. We summarize several cell surface receptors that regulate the uptake of α-syn fibrils by neurons. The aggregates are then transported along axons, both in the anterograde and retrograde direction...
March 16, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28320136/association-between-gene-polymorphism-and-depression-in-parkinson-s-disease-a-case-control-study
#2
Jinhua Zheng, Xinglong Yang, Quanzhen Zhao, Sijia Tian, Hongyan Huang, Yalan Chen, Yanming Xu
OBJECTIVE: To investigate possible associations of Parkinson's disease (PD) with polymorphism in depression-related genes and in the alpha-synuclein (SNCA) gene. METHODS: A consecutive series of patients with PD were divided into those with depression and those without it. Patients (330) were genotyped at four single-nucleotide polymorphisms (SNPs) in four genes previously associated with depression, as well as four SNPs in the PD-associated SNCA gene. RESULTS: Of 330 patients, 125 (37...
April 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28319736/structural-variants-in-snca-gene-and-the-implication-to-synucleinopathies
#3
REVIEW
Ornit Chiba-Falek
Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed of aggregates of alpha-synuclein protein. Accumulating evidence, including genome-wide association studies, has implicated the alpha-synuclein (SNCA) gene in the etiology of synucleinopathies and it has been suggested that SNCA expression levels are critical for the development of these diseases. This review focuses on genetic variants from the class of structural variants (SVs), including multiplication of large genomic segments and short (<50bp) genomic variants such as simple sequence repeats (SSRs), within the SNCA locus...
March 2, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28319654/an-alpha-synuclein-mrm-assay-with-diagnostic-potential-for-parkinson-s-disease-and-monitoring-disease-progression
#4
Li Yang, Tessandra Stewart, Min Shi, Gwenael Pottiez, Romel Dator, Rui Wu, Patrick Aro, Robert J Schuster, Carmen Ginghina, Catherine Pan, Yuqian Gao, Weijun Qian, Cyrus P Zabetian, Shu-Ching Hu, Joseph F Quinn, Jing Zhang
AIM: The alpha-synuclein (α-syn) level in human cerebrospinal fluid (CSF), as measured by immunoassays, is promising as a Parkinson's disease (PD) biomarker. However, the levels of total α-syn are inconsistent among studies with large cohorts and different measurement platforms. Total α-syn level also does not correlate with disease severity or progression. Here, we developed a highly sensitive Multiple Reaction Monitoring (MRM) method to measure absolute CSF α-syn peptide concentrations without prior enrichment or fractionation, aiming to discover new candidate biomarkers...
March 20, 2017: Proteomics. Clinical Applications
https://www.readbyqxmd.com/read/28316265/drift-diffusion-model-of-reward-and-punishment-learning-in-rare-alpha-synuclein-gene-carriers
#5
Ahmed A Moustafa, Szabolcs Kéri, Bertalan Polner, Corey White
To understand the cognitive effects of alpha-synuclein polymorphism, we employed a drift diffusion model (DDM) to analyze reward- and punishment-guided probabilistic learning task data of participants with the rare alpha-synuclein gene duplication and age- and education-matched controls. Overall, the DDM analysis showed that, relative to controls, asymptomatic alpha-synuclein gene duplication carriers had significantly increased learning from negative feedback, while they tended to show impaired learning from positive feedback...
March 20, 2017: Journal of Neurogenetics
https://www.readbyqxmd.com/read/28298083/alpha-synuclein-disease-mutations-are-structurally-defective-and-locally-affect-membrane-binding
#6
Marta Robotta, Julia Cattani, Juliana Cristina Martins, Vinod Subramaniam, Malte Drescher
The intrinsically disordered human protein alpha-Synuclein (αS) has a prominent role in Parkinson's disease (PD) pathology. Several familial variants of αS are correlated with inherited PD. Disease mutations have been shown to have an impact on lipid membrane binding. Here, using electron paramagnetic resonance spectroscopy in combination with site-directed spin labeling, we show that familial PD-associated variants are structurally defective in membrane binding and alter the local binding properties of the protein...
March 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28295625/oral-ambroxol-increases-brain-glucocerebrosidase-activity-in-a-nonhuman-primate
#7
Anna Migdalska-Richards, Wai Kin D Ko, Qin Li, Erwan Bezard, Anthony H V Schapira
Mutations in the glucocerebrosidase 1 (GBA1) gene are related to both Parkinson disease (PD) and Gaucher disease (GD). In both cases, the condition is associated with deficiency of glucocerebrosidase (GCase), the enzyme encoded by GBA1. Ambroxol is a small molecule chaperone that has been shown in mice to cross the blood-brain barrier, increase GCase activity and reduce alpha-synuclein protein levels. In this study, we analyze the effect of ambroxol treatment on GCase activity in healthy nonhuman primates. We show that daily administration of ambroxol results in increased brain GCase activity...
March 12, 2017: Synapse
https://www.readbyqxmd.com/read/28288917/cyclophilin-d-regulates-lifespan-and-protein-expression-of-aging-markers-in-the-brain-of-mice
#8
Viktoria Vereczki, Josef Mansour, Issa Pour-Ghaz, Ibolya Bodnar, Otto Pinter, Dora Zelena, Erzsebet Oszwald, Vera Adam-Vizi, Christos Chinopoulos
Cyclophilin D (cypD) modulates the properties of the permeability transition pore, a phenomenon implicated in the manifestation of many diseases including aging. Here, we examined the effects of partial or complete deletion of cypD on i) lifespan, ii) forebrain protein expression of 18 aging markers as well as regional expression of GFAP, mGluR1, and alpha-synuclein, and iii) behaviour of aged (>24month) male and female mice. Both male and female cypD heterozygous but not KO mice exhibited increased lifespans compared to WT littermates, associated with alterations in the protein expression of some markers, albeit without exhibiting changes in behaviour...
March 10, 2017: Mitochondrion
https://www.readbyqxmd.com/read/28282812/the-identification-of-alpha-synuclein-as%C3%A2-the%C3%A2-first-parkinson-disease-gene
#9
Robert L Nussbaum
In this Commentary, I describe the events that led from an NINDS-sponsored Workshop on Parkinson Disease Research in 1995, where I was asked to speak about the genetics of Parkinson disease, to the identification a mere two years later of a mutation in alpha-synuclein as the cause of autosomal dominant Parkinson disease in the Contursi kindred. I review the steps we took to first map and then find the mutation in the alpha-synuclein locus and describe the obstacles and the role of serendipity in facilitating the work...
2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28276272/gut-brain-and-brain-gut-axis-in-parkinson-s-disease-models-effects-of-a-uridine-and-fish-oil-diet
#10
Paula Perez-Pardo, Hemraj B Dodiya, Laus M Broersen, Hidde Douna, Nick van Wijk, Sofia Lopes da Silva, Johan Garssen, Ali Keshavarzian, Aletta D Kraneveld
Recent investigations have focused on the potential role of gastrointestinal (GI) abnormalities in the pathogenesis of Parkinson's disease (PD). The 'dual-hit' hypothesis of PD speculates that a putative pathogen enters the brain via two routes: the olfactory system and the GI system. Here, we investigated (1) whether local exposures of the neurotoxin rotenone in the gut or the brain of mice could induce PD-like neurological and GI phenotypes as well as a characteristic neuropathology in accordance with this 'dual-hit hypothesis' and (2) the effects of a diet containing uridine and fish oil providing docosahexaenoic acid (DHA), in both models...
March 9, 2017: Nutritional Neuroscience
https://www.readbyqxmd.com/read/28266709/bone-loss-in-c57bl-6j-olahsd-mice-a-substrain-of-c57bl-6j-carrying-mutated-alpha-synuclein-and-multimerin-1-genes
#11
Tamar Liron, Bitya Raphael, Sahar Hiram-Bab, Itai A Bab, Yankel Gabet
The inbred mouse strain C57BL/6 is commonly used for the generation of transgenic mouse and is a well-established strain in bone research. Different vendors supply different substrains of C57BL/6J as wild-type animals when genetic drift did not incur any noticeable phenotype. However, we sporadically observed drastic differences in the bone phenotype of 'WT' C57BL/6J mice originating from different labs and speculated that these variations are attributable, at least in part, to the variation between C57BL/6J substrains, which is often overlooked...
March 7, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28259991/the-involvement-of-eag1-potassium-channels-and-mir-34a-in-rotenone-induced-death-of-dopaminergic-sh-sy5y-cells
#12
Camila Hillesheim Horst, Ricardo Titze-de-Almeida, Simoneide Souza Titze-de-Almeida
The loss of dopaminergic neurons and the resultant motor impairment are hallmarks of Parkinson's disease. The SH‑SY5Y cell line is a model of dopaminergic neurons, and allows for the study of dopaminergic neuronal injury. Previous studies have revealed changes in Ether à go‑go 1 (Eag1) potassium channel expression during p53-induced SH‑SY5Y apoptosis, and the regulatory involvement of microRNA‑34a (miR‑34a) was demonstrated. In the present study, the involvement of Eag1 and miR‑34a in rotenone‑induced SH‑SY5Y cell injury was investigated...
February 10, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28257421/the-mechanism-of-sirtuin-2-mediated-exacerbation-of-alpha-synuclein-toxicity-in-models-of-parkinson-disease
#13
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, 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
Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies...
March 2017: PLoS Biology
https://www.readbyqxmd.com/read/28257086/high-throughput-screening-methodology-to-identify-alpha-synuclein-aggregation-inhibitors
#14
Jordi Pujols, Samuel Peña-Díaz, María Conde-Giménez, Francisca Pinheiro, Susanna Navarro, Javier Sancho, Salvador Ventura
An increasing number of neurodegenerative diseases are being found to be associated with the abnormal accumulation of aggregated proteins in the brain. In Parkinson's disease, this process involves the aggregation of alpha-synuclein (α-syn) into intraneuronal inclusions. Thus, compounds that inhibit α-syn aggregation represent a promising therapeutic strategy as disease-modifying agents for neurodegeneration. The formation of α-syn amyloid aggregates can be reproduced in vitro by incubation of the recombinant protein...
March 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28256519/autophagy-down-regulates-pro-inflammatory-mediators-in-bv2-microglial-cells-and-rescues-both-lps-and-alpha-synuclein-induced-neuronal-cell-death
#15
Claudio Bussi, Javier Maria Peralta Ramos, Daniela S Arroyo, Emilia A Gaviglio, Jose Ignacio Gallea, Ji Ming Wang, Maria Soledad Celej, Pablo Iribarren
Autophagy is a fundamental cellular homeostatic mechanism, whereby cells autodigest parts of their cytoplasm for removal or turnover. Neurodegenerative disorders are associated with autophagy dysregulation, and drugs modulating autophagy have been successful in several animal models. Microglial cells are phagocytes in the central nervous system (CNS) that become activated in pathological conditions and determine the fate of other neural cells. Here, we studied the effects of autophagy on the production of pro-inflammatory molecules in microglial cells and their effects on neuronal cells...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28239455/the-underlying-mechanism-of-prodromal-pd-insights-from-the-parasympathetic-nervous-system-and-the-olfactory-system
#16
REVIEW
Shu-Ying Liu, Piu Chan, A Jon Stoessl
Neurodegeneration of Parkinson's disease (PD) starts in an insidious manner, 30-50% of dopaminergic neurons have been lost in the substantia nigra before clinical diagnosis. Prodromal stage of the disease, during which the disease pathology has started but is insufficient to result in clinical manifestations, offers a valuable window for disease-modifying therapies. The most focused underlying mechanisms linking the pathological pattern and clinical characteristics of prodromal PD are the prion hypothesis of alpha-synuclein and the selective vulnerability of neurons...
2017: Translational Neurodegeneration
https://www.readbyqxmd.com/read/28236005/pure-autonomic-failure-without-alpha-synuclein-pathology-an-evolving-understanding-of-a-heterogeneous-disease
#17
EDITORIAL
Elizabeth A Coon, Phillip A Low
No abstract text is available yet for this article.
February 24, 2017: Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society
https://www.readbyqxmd.com/read/28224980/alpha-synuclein-prevents-the-formation-of-spherical-mitochondria-and-apoptosis-under-oxidative-stress
#18
Stefanie Menges, Georgia Minakaki, Patrick M Schaefer, Holger Meixner, Iryna Prots, Ursula Schlötzer-Schrehardt, Kristina Friedland, Beate Winner, Tiago F Outeiro, Konstanze F Winklhofer, Christine A F von Arnim, Wei Xiang, Jürgen Winkler, Jochen Klucken
Oxidative stress (OS), mitochondrial dysfunction, and dysregulation of alpha-synuclein (aSyn) homeostasis are key pathogenic factors in Parkinson's disease. Nevertheless, the role of aSyn in mitochondrial physiology remains elusive. Thus, we addressed the impact of aSyn specifically on mitochondrial response to OS in neural cells. We characterize a distinct type of mitochondrial fragmentation, following H2O2 or 6-OHDA-induced OS, defined by spherically-shaped and hyperpolarized mitochondria, termed "mitospheres"...
February 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28218419/alpha-synuclein-fibrils-propagate-through-tunneling-nanotubes
#19
Shinya Okuda, Norihito Uemura, Ryosuke Takahashi
No abstract text is available yet for this article.
February 20, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28217760/sleep-in-alzheimer-s-disease-beyond-amyloid
#20
Jerrah Holth, Tirth Patel, David M Holtzman
Sleep disorders are prevalent in Alzheimer's disease (AD) and a major cause of institutionalization. Like AD pathology, sleep abnormalities can appear years before cognitive decline and may be predictive of dementia. A bidirectional relationship between sleep and amyloid β (Aβ) has been well established with disturbed sleep and increased wakefulness leading to increased Aβ production and decreased Aβ clearance; whereas Aβ deposition is associated with increased wakefulness and sleep disturbances. Aβ fluctuates with the sleep wake cycle and is higher during wakefulness and lower during sleep...
January 2017: Neurobiology of Sleep and Circadian Rhythms
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