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https://www.readbyqxmd.com/read/28324300/%C3%AE-synuclein-and-parkinsonism-updates-and-future-perspectives
#1
REVIEW
Kaie Rosborough, Neha Patel, Lorraine V Kalia
Mutations in the SNCA gene, which encodes the α-synuclein protein, were the first discovered genetic causes of familial parkinsonism with Lewy pathology. To date, six different SNCA missense mutations as well as multiplications are known to cause parkinsonism. For this review, we performed a literature search to identify all published cases of SNCA-related parkinsonism to provide an updated summary of the clinical and neuropathological features of parkinsonism due to SNCA mutations. Familial parkinsonism associated with SNCA is rare, but α-synuclein aggregation is a core feature of sporadic parkinsonism, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy...
April 2017: Current Neurology and Neuroscience Reports
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/28315001/ltb-syn-a-recombinant-immunogen-for-the-development-of-plant-made-vaccines-against-synucleinopathies
#6
Jaime I Arevalo-Villalobos, Dania O Govea-Alonso, Elizabeth Monreal-Escalante, Sergio Zarazúa, Sergio Rosales-Mendoza
A recombinant antigen targeting α-synuclein was produced in the plant cell rendering an immunogenic protein capable to induce humoral responses in mice upon oral administration. Synucleinopathies are neurodegenerative diseases characterized by the abnormal accumulation of α-synuclein (α-Syn, a 140 amino acid protein that normally plays various neurophysiologic roles) aggregates. Parkinson's disease (PD) is the synucleinopathy with the highest epidemiologic impact and although its etiology remains unknown, α-Syn aggregation during disease progression pointed out α-Syn as target in the development of immunotherapies...
March 17, 2017: Planta
https://www.readbyqxmd.com/read/28303260/evidence-for-an-additive-neurorestorative-effect-of-simultaneously-administered-cdnf-and-gdnf-in-hemiparkinsonian-rats-implications-for-different-mechanism-of-action
#7
Merja H Voutilainen, Francesca De Lorenzo, Polina Stepanova, Susanne Bäck, Li-Ying Yu, Päivi Lindholm, Eeva Pörsti, Mart Saarma, Pekka T Männistö, Raimo K Tuominen
Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic (DAergic) neurons of the substantia nigra (SN) and the accumulation of intracellular inclusions containing α-synuclein. Current therapies do not stop the progression of the disease, and the efficacy of these treatments wanes over time. Neurotrophic factors (NTFs) are naturally occurring proteins promoting the survival and differentiation of neurons and the maintenance of neuronal contacts. CDNF (cerebral dopamine NTF) and GDNF (glial cell line-derived NTF) are able to protect DAergic neurons against toxin-induced degeneration in experimental models of PD...
January 2017: ENeuro
https://www.readbyqxmd.com/read/28300150/s-nitrosylation-of-uchl1-induces-its-structural-instability-and-promotes-%C3%AE-synuclein-aggregation
#8
Roshan Kumar, Deepak K Jangir, Garima Verma, Shashi Shekhar, Pranita Hanpude, Sanjay Kumar, Raniki Kumari, Nirpendra Singh, Neel Sarovar Bhavesh, Nihar Ranjan Jana, Tushar Kanti Maiti
Ubiquitin C-terminal Hydrolase-1 (UCHL1) is a deubiquitinating enzyme, which plays a key role in Parkinson's disease (PD). It is one of the most important proteins, which constitute Lewy body in PD patient. However, how this well folded highly soluble protein presents in this proteinaceous aggregate is still unclear. We report here that UCHL1 undergoes S-nitrosylation in vitro and rotenone induced PD mouse model. The preferential nitrosylation in the Cys 90, Cys 152 and Cys 220 has been observed which alters the catalytic activity and structural stability...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28300069/extracellular-%C3%AE-synuclein-induces-sphingosine-1-phosphate-receptor-subtype-1-uncoupled-from-inhibitory-g-protein-leaving-%C3%AE-arrestin-signal-intact
#9
Lifang Zhang, Taro Okada, Shaymaa Mohamed Mohamed Badawy, Chihoko Hirai, Taketoshi Kajimoto, Shun-Ichi Nakamura
Parkinson's disease (PD) is the second most common neurodegenerative disorder. The presence of α-synuclein (α-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies, is the cytopathological hallmark of PD. Increasing bodies of evidence suggest that cell-to-cell transmission of α-Syn plays a role in the progression of PD. Although extracellular α-Syn is known to cause abnormal cell motility, the precise mechanism remains elusive. Here we show that impairment of platelet-derived growth factor-induced cell motility caused by extracellular α-Syn is mainly attributed to selective inhibition of sphingosine 1-phosphate (S1P) signalling...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28298083/alpha-synuclein-disease-mutations-are-structurally-defective-and-locally-affect-membrane-binding
#10
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/28297586/the-cleavage-effect-of-mesenchymal-stem-cell-and-its-derived-matrix-metalloproteinase-2-on-extracellular-%C3%AE-synuclein-aggregates-in-parkinsonian-models
#11
Se Hee Oh, Ha Na Kim, Hyun Jung Park, Jin Young Shin, Dong Yeol Kim, Phil Hyu Lee
Ample evidence has suggested that extracellular α-synuclein aggregates would play key roles in the pathogenesis and progression of Parkinsonian disorders (PDs). In the present study, we investigated whether mesenchymal stem cells (MSCs) and their derived soluble factors could exert neuroprotective effects via proteolysis of extracellular α-synuclein. When preformed α-synuclein aggregates were incubated with MSC-conditioned medium, α-synuclein aggregates were disassembled, and insoluble and oligomeric forms of α-synuclein were markedly decreased, thus leading to a significant increase in neuronal viability...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28295625/oral-ambroxol-increases-brain-glucocerebrosidase-activity-in-a-nonhuman-primate
#12
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/28292328/age-dependent-dopamine-transporter-dysfunction-and-serine129-phospho-%C3%AE-synuclein-overload-in-g2019s-lrrk2-mice
#13
Francesco Longo, Daniela Mercatelli, Salvatore Novello, Ludovico Arcuri, Alberto Brugnoli, Fabrizio Vincenzi, Isabella Russo, Giulia Berti, Omar S Mabrouk, Robert T Kennedy, Derya R Shimshek, Katia Varani, Luigi Bubacco, Elisa Greggio, Michele Morari
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease. Here, we investigated whether the G2019S LRRK2 mutation causes morphological and/or functional changes at nigro-striatal dopamine neurons. Density of striatal dopaminergic terminals, nigral cell counts, tyrosine hydroxylase protein levels as well as exocytotic dopamine release measured in striatal synaptosomes, or striatal extracellular dopamine levels monitored by in vivo microdialysis were similar between ≥12-month-old G2019S knock-in mice and wild-type controls...
March 14, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28292187/distinct-mechanisms-determine-%C3%AE-synuclein-fibril-morphology-during-growth-and-maturation
#14
Arshdeep Sidhu, Ine Segers-Nolten, Vincent Raussens, Mireille M A E Claessens, Vinod Subramaniam
Amyloid polymorphs have become one of the focal points of molecular studies of neurodegenerative diseases like Parkinson's disease. Due to their distinct biochemical properties and prion-like characteristics, insights into the molecular origin and stability of amyloid polymorphs over time are crucial for understanding the potential role of amyloid polymorphism in these diseases. Here, we systematically study the fibrillization of recombinantly produced human α-synuclein (αSyn) over an extended period of time to unravel the origin and temporal evolution of polymorphism...
March 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28289488/copper-ii-and-the-pathological-h50q-%C3%AE-synuclein-mutant-environment-meets-genetics
#15
COMMENT
Anna Villar-Piqué, Giulia Rossetti, Salvador Ventura, Paolo Carloni, Claudio O Fernández, Tiago Fleming Outeiro
Copper is one of the metals described to bind the Parkinson disease-related protein α-synuclein (aSyn), and to promote its aggregation. Although histidine at position 50 in the aSyn sequence is one of the most studied copper-anchoring sites, its precise role in copper binding and aSyn aggregation is still unclear. Previous studies suggested that this residue does not significantly affect copper-mediated aSyn aggregation. However, our findings showed that the aggregation of the pathological H50Q aSyn mutant is enhanced by copper hints otherwise...
2017: Communicative & Integrative Biology
https://www.readbyqxmd.com/read/28289371/exosomes-origins-and-therapeutic-potential-for-neurodegenerative-disease
#16
REVIEW
Diana K Sarko, Cindy E McKinney
Exosomes, small lipid bilayer vesicles, are part of the transportable cell secretome that can be taken up by nearby recipient cells or can travel through the bloodstream to cells in distant organs. Selected cellular cytoplasm containing proteins, RNAs, and other macromolecules is packaged into secreted exosomes. This cargo has the potential to affect cellular function in either healthy or pathological ways. Exosomal content has been increasingly shown to assist in promoting pathways of neurodegeneration such as β-amyloid peptide (Aβ) accumulation forming amyloid plaques in the brains of patients with Alzheimer's disease, and pathological aggregates of proteins containing α-synuclein in Parkinson's disease transferred to the central nervous system via exosomes...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28288917/cyclophilin-d-regulates-lifespan-and-protein-expression-of-aging-markers-in-the-brain-of-mice
#17
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/28288262/aggregation-of-%C3%AE-synuclein-in-the-gonadal-tissue-of-2-patients-with-parkinson-disease
#18
Alicia Garrido, Iban Aldecoa, Ellen Gelpi, Eduardo Tolosa
No abstract text is available yet for this article.
March 13, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/28288128/%C3%AE-synuclein-promotes-dilation-of-the-exocytotic-fusion-pore
#19
Todd Logan, Jacob Bendor, Chantal Toupin, Kurt Thorn, Robert H Edwards
The protein α-synuclein has a central role in the pathogenesis of Parkinson's disease. Like that of other proteins that accumulate in neurodegenerative disease, however, the function of α-synuclein remains unknown. Localization to the nerve terminal suggests a role in neurotransmitter release, and overexpression inhibits regulated exocytosis, but previous work has failed to identify a clear physiological defect in mice lacking all three synuclein isoforms. Using adrenal chromaffin cells and neurons, we now find that both overexpressed and endogenous synuclein accelerate the kinetics of individual exocytotic events, promoting cargo discharge and reducing pore closure ('kiss-and-run')...
March 13, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28283027/integrated-analysis-of-genetic-behavioral-and-biochemical-data-implicates-neural-stem-cell-induced-changes-in-immunity-neurotransmission-and-mitochondrial-function-in-dementia-with-lewy-body-mice
#20
Anita Lakatos, Natalie R S Goldberg, Mathew Blurton-Jones
We previously demonstrated that transplantation of murine neural stem cells (NSCs) can improve motor and cognitive function in a transgenic model of Dementia with Lewy Bodies (DLB). These benefits occurred without changes in human α-synuclein pathology and were mediated in part by stem cell-induced elevation of brain-derived neurotrophic factor (BDNF). However, instrastriatal NSC transplantation likely alters the brain microenvironment via multiple mechanisms that may synergize to promote cognitive and motor recovery...
March 10, 2017: Acta Neuropathologica Communications
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