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https://www.readbyqxmd.com/read/28736850/progressive-ataxia-and-palatal-tremor-two-autopsy-cases-of-a-novel-tauopathy
#1
Andrew F Gao, Achinoam Faust-Socher, Maryam Al-Murshed, Marc R Del Bigio, Anthony E Lang, David G Munoz
BACKGROUND: Sporadic progressive ataxia and palatal tremor is a rare syndrome characterized by mid- to late-adult-onset symptomatic palatal tremor and slowly progressive cerebellar ataxia. To date, there has been only one autopsy report, which described a novel 4-repeat tauopathy with hypertrophic olivary degeneration and tau-positive inclusions in olivary neurons and dystrophic neuritic processes termed glomeruloid bodies. We report on 2 additional autopsy cases. METHODS: Sections from selected paraffin-embedded brain regions were stained with hematoxylin and eosin/Luxol fast blue and processed for phosphorylated tau, 3-repeat tau, 4-repeat tau, neurofilament, glial fibrillary acid protein, phosphorylated α-synuclein, phosphorylated TAR DNA-binding protein 43, beta-amyloid, and p62 immunohistochemistry...
July 24, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28736195/allelic-difference-in-mhc2ta-confers-altered-microglial-activation-and-susceptibility-to-%C3%AE-synuclein-induced-dopaminergic-neurodegeneration
#2
Itzia Jimenez-Ferrer, Michael Jewett, Ashmita Tontanahal, Marina Romero-Ramos, Maria Swanberg
Parkinson Disease (PD) is a complex and heterogeneous neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta and pathological intracellular accumulation of alpha-synuclein (α-syn). In the vast majority of PD patients, the disease has a complex etiology, defined by multiple genetic and environmental risk factors. Common genetic variants in the human leukocyte-antigen (HLA) region have been associated to PD risk and the carriage of these can double the risk to develop PD...
July 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28734051/a-user-s-guide-for-%C3%AE-synuclein-biomarker-studies-in-biological-fluids-perianalytical-considerations
#3
REVIEW
Brit Mollenhauer, Richard Batrla, Omar El-Agnaf, Douglas R Galasko, Hilal A Lashuel, Kalpana M Merchant, Lesley M Shaw, Dennis J Selkoe, Robert Umek, Hugo Vanderstichele, Henrik Zetterberg, Jing Zhang, Chelsea Caspell-Garcia, Chris Coffey, Samantha J Hutten, Mark Frasier, Peggy Taylor
Parkinson's disease biomarkers are needed to increase diagnostic accuracy, to objectively monitor disease progression and to assess therapeutic efficacy as well as target engagement when evaluating novel drug and therapeutic strategies. This article summarizes perianalytical considerations for biomarker studies (based on immunoassays) in Parkinson's disease, with emphasis on quantifying total α-synuclein protein in biological fluids. Current knowledge and pitfalls are discussed, and selected perianalytical variables are presented systematically, including different temperature of sample collection and types of collection tubes, gradient sampling, the addition of detergent, aliquot volume, the freezing time, and the different thawing methods...
July 22, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28732710/cytokine-profiling-in-the-prefrontal-cortex-of-parkinson-s-disease-and-multiple-system-atrophy-patients
#4
Rasmus Rydbirk, Betina Elfving, Mille Dahl Andersen, Mia Aggergaard Langbøl, Jonas Folke, Kristian Winge, Bente Pakkenberg, Tomasz Brudek, Susana Aznar
Parkinson's Disease (PD) and Multiple System Atrophy (MSA) are neurodegenerative diseases characterized neuropathologically by alpha-synuclein accumulation in brain cells. This accumulation is hypothesized to contribute to constitutive neuroinflammation, and to participate in the neurodegeneration. Cytokines, which are the main inflammatory signalling molecules, have been identified in blood and cerebrospinal fluid of PD patients, but studies investigating the human brain levels are scarce. It is documented that neurotrophins, necessary for survival of brain cells and known to interact with cytokines, are altered in the basal ganglia of PD patients...
July 18, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28731447/chromatin-bound-oxidized-%C3%AE-synuclein-causes-strand-breaks-in-neuronal-genomes-in-in-vitro-models-of-parkinson-s-disease
#5
Velmarini Vasquez, Joy Mitra, Pavana M Hegde, Arvind Pandey, Shiladitya Sengupta, Sankar Mitra, K S Rao, Muralidhar L Hegde
Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson's disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis...
July 17, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28729832/the-role-of-microglia-in-retinal-neurodegeneration-alzheimer-s-disease-parkinson-and-glaucoma
#6
REVIEW
Ana I Ramirez, Rosa de Hoz, Elena Salobrar-Garcia, Juan J Salazar, Blanca Rojas, Daniel Ajoy, Inés López-Cuenca, Pilar Rojas, Alberto Triviño, José M Ramírez
Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28725967/%C3%AE-synuclein-transfer-between-neurons-and-astrocytes-indicates-that-astrocytes-play-a-role-in-degradation-rather-than-in-spreading
#7
Frida Loria, Jessica Y Vargas, Luc Bousset, Sylvie Syan, Audrey Salles, Ronald Melki, Chiara Zurzolo
Recent evidence suggests that disease progression in Parkinson's disease (PD) could occur by the spreading of α-synuclein (α-syn) aggregates between neurons. Here we studied the role of astrocytes in the intercellular transfer and fate of α-syn fibrils, using in vitro and ex vivo models. α-Syn fibrils can be transferred to neighboring cells; however, the transfer efficiency changes depending on the cell types. We found that α-syn is efficiently transferred from astrocytes to astrocytes and from neurons to astrocytes, but less efficiently from astrocytes to neurons...
July 19, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28724388/o-glcnac-regulation-of-autophagy-and-%C3%AE-synuclein-homeostasis-implications-for-parkinson-s-disease
#8
Willayat Y Wani, Xiaosen Ouyang, Gloria A Benavides, Matthew Redmann, Stacey S Cofield, John J Shacka, John C Chatham, Victor Darley-Usmar, Jianhua Zhang
Post-translational modification on protein Ser/Thr residues by O-linked attachment of ß-N-acetyl-glucosamine (O-GlcNAcylation) is a key mechanism integrating redox signaling, metabolism and stress responses. One of the most common neurodegenerative diseases that exhibit aberrant redox signaling, metabolism and stress response is Parkinson's disease, suggesting a potential role for O-GlcNAcylation in its pathology. To determine whether abnormal O-GlcNAcylation occurs in Parkinson's disease, we analyzed lysates from the postmortem temporal cortex of Parkinson's disease patients and compared them to age matched controls and found increased protein O-GlcNAcylation levels...
July 19, 2017: Molecular Brain
https://www.readbyqxmd.com/read/28722658/the-golgi-localized-gamma-ear-containing-arf-binding-gga-protein-family-alters-alpha-synuclein-%C3%AE-syn-oligomerization-and-secretion
#9
Bjoern von Einem, Judith Eschbach, Martin Kiechle, Anke Wahler, Dietmar R Thal, Pamela J McLean, Jochen H Weishaupt, Albert C Ludolph, Christine A F von Arnim, Karin M Danzer
Several age-related neurodegenerative disorders are associated with protein misfolding and aggregation of toxic peptides. α-synuclein (α-syn) aggregation and the resulting cytotoxicity is a hallmark of Parkinson's disease (PD) as well as dementia with Lewy bodies. Rising evidence points to oligomeric and pre-fibrillar forms as the pathogenic species, and oligomer secretion seems to be crucial for the spreading and progression of PD pathology. Recent studies implicate that dysfunctions in endolysosomal/autophagosomal pathways increase α-syn secretion...
July 15, 2017: Aging
https://www.readbyqxmd.com/read/28715596/influence-of-physical-exercise-on-%C3%AE-amyloid-%C3%AE-synuclein-and-tau-accumulation-an-in-vitro-model-of-oxidative-stress-in-human-red-blood-cells
#10
C Iofrida, S Daniele, D Pietrobono, J Fusi, F Galetta, M L Trincavelli, U Bonuccelli, F Franzoni, C Martini
A common pathological feature of neurodegenerative disorders (NDs), such as Alzheimer's (AD) and Parkinson's (PD) diseases, is the abnormal accumulation and misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1-42 (Aβ) and tau, in brain and in peripheral tissues too. Oxidative stress has been proved to be involved in NDs at various levels and, in particular, in such protein alterations, on the contrary physical activity is emerging as a counteracting factor in NDs. In the present work, the content of Aβ, α-syn and tau in red blood cells (RBCs) derived from ten endurance athletes (ATHL) and ten sedentary volunteers (SED) were compared before and after in vitrooxidative stress treatment...
July 1, 2017: Archives Italiennes de Biologie
https://www.readbyqxmd.com/read/28713240/the-coordinated-action-of-calcineurin-and-cathepsin-d-protects-against-%C3%AE-synuclein-toxicity
#11
Andreas Aufschnaiter, Lukas Habernig, Verena Kohler, Jutta Diessl, Didac Carmona-Gutierrez, Tobias Eisenberg, Walter Keller, Sabrina Büttner
The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of α-synuclein (αSyn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of αSyn has been attributed to disturbances in several biological processes conserved from yeast to humans, including Ca(2+) homeostasis, general lysosomal function and autophagy. However, the precise sequence of events that eventually results in cell death remains unclear...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28711409/nortriptyline-inhibits-aggregation-and-neurotoxicity-of-alpha-synuclein-by-enhancing-reconfiguration-of-the-monomeric-form
#12
Timothy J Collier, Kinshuk R Srivastava, Craig Justman, Tom Grammatopoulous, Birgit Hutter-Paier, Manuela Prokesch, Daniel Havas, Jean-Christophe Rochet, Fang Liu, Kevin Jock, Patrícia de Oliveira, Georgia L Stirtz, Ulf Dettmer, Caryl E Sortwell, Mel B Feany, Peter Lansbury, Lisa Lapidus, Katrina L Paumier
The pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar α-synuclein (α-syn). One strategy to slow disease progression is to prevent the misfolding and aggregation of its native monomeric form. Here we present findings that support the contention that the tricyclic antidepressant compound nortriptyline (NOR) has disease-modifying potential for synucleinopathies. Findings from in vitro aggregation and kinetics assays support the view that NOR inhibits aggregation of α-syn by directly binding to the soluble, monomeric form, and by enhancing reconfiguration of the monomer, inhibits formation of toxic conformations of the protein...
July 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28711405/a-unique-glycan-isoform-of-transferrin-in-cerebrospinal-fluid-a-potential-diagnostic-marker-for-neurological-diseases
#13
REVIEW
Kyoka Hoshi, Hiromi Ito, Yuka Matsumoto, Kiyoshi Saito, Takashi Honda, Yoshiki Yamaguchi, Yasuhiro Hashimoto
BACKGROUND: cerebrospinal fluid (CSF) is sequestered from blood by the blood-brain barrier and directly communicates with brain parenchymal interstitial fluid, leading to contain specific biomarkers of neurological diseases. SCOPE OF REVIEW: CSF contains glycan isoforms of transferrin (Tf): one appears to be derived from the brain and the other from blood. MAJOR CONCLUSIONS: CSF contains two glycan-isoforms; brain-type Tf and serum-type Tf...
July 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28710275/a-ph-dependent-switch-promotes-%C3%AE-synuclein-fibril-formation-via-glutamate-residues
#14
Gina M Moriarty, Michael P Olson, Tamr B Atieh, Maria K Janowska, Sagar D Khare, Jean Baum
Alpha-synuclein (αS) is the primary protein associated with Parkinson's disease, and undergoes aggregation from its intrinsically disordered monomeric form to a cross-β fibrillar form. The closely related homolog beta-synuclein (βS) is essentially fibril resistant under cytoplasmic physiological conditions. Toxic gain of function by βS has been linked to dysfunction, but the aggregation behavior of βS under altered pH is not well understood. In this work, we compare fibril formation of αS and βS at pH 7...
July 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28706191/aldehyde-dehydrogenase-1-positive-nigrostriatal-dopaminergic-fibers-exhibit-distinct-projection-pattern-and-dopamine-release-dynamics-at-mouse-dorsal-striatum
#15
Carmelo Sgobio, Junbing Wu, Wang Zheng, Xi Chen, Jing Pan, Armando G Salinas, Margaret I Davis, David M Lovinger, Huaibin Cai
Aldehyde dehydrogenase 1 (ALDH1A1)-positive dopaminergic (DA) neurons at the ventral substantia nigra pars compacta (SNpc) preferentially degenerate in Parkinson's disease (PD). Their projection pattern and dopamine release properties, however, remains uncharacterized. Here we show that ALDH1A1-positive axons project predominantly to the rostral two-thirds of dorsal striatum. A portion of these axons converge on a small fraction of striosome compartments restricted to the dorsolateral striatum (DLS), where less dopamine release was measured compared to the adjacent matrix enriched with the ALDH1A1-negative axons...
July 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28702523/implications-of-peptide-assemblies-in-amyloid-diseases
#16
REVIEW
Pu Chun Ke, Marc-Antonie Sani, Feng Ding, Aleksandr Kakinen, Ibrahim Javed, Frances Separovic, Thomas P Davis, Raffaele Mezzenga
Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology - much of which are poorly understood - these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer's, Parkinson's, type 2 diabetes and prion diseases...
July 12, 2017: Chemical Society Reviews
https://www.readbyqxmd.com/read/28698628/%C3%AE-synuclein-control-of-mitochondrial-homeostasis-in-human-derived-neurons-is-disrupted-by-mutations-associated-with-parkinson-s-disease
#17
Victorio Martin Pozo Devoto, Nicolas Dimopoulos, Matías Alloatti, María Belén Pardi, Trinidad M Saez, María Gabriela Otero, Lucas Eneas Cromberg, Antonia Marín-Burgin, Maria Elida Scassa, Gorazd B Stokin, Alejandro F Schinder, Gustavo Sevlever, Tomás Luis Falzone
The etiology of Parkinson's disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown. Here, we analyzed mitochondrial axonal transport and morphology in human-derived neurons overexpressing wild-type (WT) αSyn or the mutated variants A30P or A53T, which are known to have differential lipid affinities...
July 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28698377/monomeric-and-fibrillar-%C3%AE-synuclein-exert-opposite-effects-on-the-catalytic-cycle-that-promotes-the-proliferation-of-a%C3%AE-42-aggregates
#18
Sean Chia, Patrick Flagmeier, Johnny Habchi, Veronica Lattanzi, Sara Linse, Christopher M Dobson, Tuomas P J Knowles, Michele Vendruscolo
The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by demonstrating that different structural forms of α-synuclein exert different effects on Aβ aggregation. Our results demonstrate that whereas monomeric α-synuclein blocks the autocatalytic proliferation of Aβ42 (the 42-residue form of Aβ) fibrils, fibrillar α-synuclein catalyses the heterogeneous nucleation of Aβ42 aggregates...
July 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28696461/room-temperature-in-cell-epr-spectroscopy-alpha-synuclein-disease-variants-remain-intrinsically-disordered-in-the-cell
#19
Julia Cattani, Vinod Subramaniam, Malte Drescher
Human alpha-Synuclein (aS), implicated in Parkinson's disease, adopts a rich variety of different conformations depending on the macromolecular context. In order to unravel its pathophysiological role, monitoring its intracellular conformational state and identifying differences for the disease variants is crucial. Here, we present an intracellular spectroscopy approach based on a systematic spin-labeling site-scan in combination with intracellular electron paramagnetic resonance spectroscopy determining conformations on a molecular scale...
July 11, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28696167/neuroprotective-effect-of-%C3%AE-mangostin-on-mitochondrial-dysfunction-and-%C3%AE-synuclein-aggregation-in-rotenone-induced-model-of-parkinson-s-disease-in-differentiated-sh-sy5y-cells
#20
Xin-Mei Hao, Lian-Da Li, Chang-Ling Duan, Yu-Juan Li
The study was designed to evaluate the protective effect of α-mangostin and explore its mechanism in an in vitro model of Parkinson's disease (PD) induced by rotenone. SH-SY5Y cells were treated with rotenone and α-mangostin for 24 h. α-Mangostin significantly and concentration-dependently inhibited rotenone-induced cytotoxicity. The rotenone-induced aggregation of α-synuclein and loss of TH were alleviated by α-mangostin. α-Mangostin treatment also reversed the rotenone-induced overproduction of reactive oxygen species, activation of caspases (-8 and -3) and mitochondrial dysfunction, reflected by decrease in mitochondrial membrane potential and cellular ATP levels...
August 2017: Journal of Asian Natural Products Research
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