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https://www.readbyqxmd.com/read/28922846/different-complicated-brain-pathologies-in-monozygotic-twins-with-gerstmann-str%C3%A3-ussler-scheinker-disease
#1
Hiroyuki Honda, Kensuke Sasaki, Hiroshi Takashima, Daisuke Mori, Sachiko Koyama, Satoshi O Suzuki, Toru Iwaki
Gerstmann-Sträussler-Scheinker disease (GSS) is an autosomal, dominantly inherited prion disease. In this study, we present different complicated brain pathologies determined postmortem of monozygotic GSS twin sisters. Case 1 showed cerebellar ataxia at the age of 58 years, and died at 66 years. Case 2 became symptomatic at the age of 75 years, and died at 79 years. There was a 17-year difference in the age of onset between the twins. Postmortem examination revealed numerous prion protein (PrP) plaques in the brains of both cases...
October 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28910367/a-novel-panel-of-%C3%AE-synuclein-antibodies-reveal-distinctive-staining-profiles-in-synucleinopathies
#2
Jess-Karan S Dhillon, Cara Riffe, Brenda D Moore, Yong Ran, Paramita Chakrabarty, Todd E Golde, Benoit I Giasson
Synucleinopathies are a spectrum of neurodegenerative diseases characterized by the intracellular deposition of the protein α-synuclein leading to multiple outcomes, including dementia and Parkinsonism. Recent findings support the notion that across the spectrum of synucleinopathies there exist diverse but specific biochemical modifications and/or structural conformations of α-synuclein, which would give rise to protein strain specific prion-like intercellular transmission, a proposed model that could explain synucleinopathies disease progression...
2017: PloS One
https://www.readbyqxmd.com/read/28904388/protective-efficacy-of-phosphodiesterase-1-inhibition-against-alpha-synuclein-toxicity-revealed-by-compound-screening-in-luhmes-cells
#3
Matthias Höllerhage, Claudia Moebius, Johannes Melms, Wei-Hua Chiu, Joachim N Goebel, Tasnim Chakroun, Thomas Koeglsperger, Wolfgang H Oertel, Thomas W Rösler, Marc Bickle, Günter U Höglinger
α-synuclein-induced neurotoxicity is a core pathogenic event in neurodegenerative synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs for their efficacy to protect LUHMES cells from degeneration induced by wild-type α-synuclein and identified dipyridamole, a non-selective phosphodiesterase inhibitor, as top hit. Systematic analysis of other phosphodiesterase inhibitors identified a specific phosphodiesterase 1 inhibitor as most potent to rescue from α-synuclein toxicity...
September 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28903781/transmission-of-%C3%AE-synuclein-containing-erythrocyte-derived-extracellular-vesicles-across-the-blood-brain-barrier-via-adsorptive-mediated-transcytosis-another-mechanism-for-initiation-and-progression-of-parkinson-s-disease
#4
Junichi Matsumoto, Tessandra Stewart, Lifu Sheng, Na Li, Kristin Bullock, Ning Song, Min Shi, William A Banks, Jing Zhang
Parkinson's disease (PD) pathophysiology develops in part from the formation, transmission, and aggregation of toxic species of the protein α-synuclein (α-syn). Recent evidence suggests that extracellular vesicles (EVs) may play a vital role in the transport of toxic α-syn between brain regions. Moreover, increasing evidence has highlighted the participation of peripheral molecules, particularly inflammatory species, which may influence or exacerbate the development of PD-related changes to the central nervous system (CNS), although detailed characterization of these species remains to be completed...
September 13, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28900007/e46k-%C3%AE-synuclein-pathological-mutation-causes-cell-autonomous-toxicity-without-altering-protein-turnover-or-aggregation
#5
Ignacio Íñigo-Marco, Miguel Valencia, Laura Larrea, Ricardo Bugallo, Mikel Martínez-Goikoetxea, Iker Zuriguel, Montserrat Arrasate
α-Synuclein (aSyn) is the main driver of neurodegenerative diseases known as "synucleinopathies," but the mechanisms underlying this toxicity remain poorly understood. To investigate aSyn toxic mechanisms, we have developed a primary neuronal model in which a longitudinal survival analysis can be performed by following the overexpression of fluorescently tagged WT or pathologically mutant aSyn constructs. Most aSyn mutations linked to neurodegenerative disease hindered neuronal survival in this model; of these mutations, the E46K mutation proved to be the most toxic...
September 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28900002/modeling-parkinson-s-disease-pathology-by-combination-of-fibril-seeds-and-%C3%AE-synuclein-overexpression-in-the-rat-brain
#6
Poonam Thakur, Ludivine S Breger, Martin Lundblad, Oi Wan Wan, Bengt Mattsson, Kelvin C Luk, Virginia M Y Lee, John Q Trojanowski, Anders Björklund
Although a causative role of α-synuclein (α-syn) is well established in Parkinson's disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson's disease by injecting human α-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human α-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration...
September 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28883518/new-compounds-identified-through-in-silico-approaches-reduce-the-%C3%AE-synuclein-expression-by-inhibiting-prolyl-oligopeptidase-in-vitro
#7
Raj Kumar, Rohit Bavi, Min Gi Jo, Venkatesh Arulalapperumal, Ayoung Baek, Shailima Rampogu, Myeong Ok Kim, Keun Woo Lee
Prolyl oligopeptidase (POP) is a serine protease that is responsible for the maturation and degradation of short neuropeptides and peptide hormones. The inhibition of POP has been demonstrated in the treatment of α-synucleinopathies and several neurological conditions. Therefore, ligand-based and structure-based pharmacophore models were generated and validated in order to identify potent POP inhibitors. Pharmacophore-based and docking-based virtual screening of a drug-like database resulted in 20 compounds...
September 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28882452/aav-php-b-mediated-global-scale-expression-in-the-mouse-nervous-system-enables-gba1-gene-therapy-for-wide-protection-from-synucleinopathy
#8
Giuseppe Morabito, Serena G Giannelli, Gabriele Ordazzo, Simone Bido, Valerio Castoldi, Marzia Indrigo, Tommaso Cabassi, Stefano Cattaneo, Mirko Luoni, Cinzia Cancellieri, Alessandro Sessa, Marco Bacigaluppi, Stefano Taverna, Letizia Leocani, José L Lanciego, Vania Broccoli
The lack of technology for direct global-scale targeting of the adult mouse nervous system has hindered research on brain processing and dysfunctions. Currently, gene transfer is normally achieved by intraparenchymal viral injections, but these injections target a restricted brain area. Herein, we demonstrated that intravenous delivery of adeno-associated virus (AAV)-PHP.B viral particles permeated and diffused throughout the neural parenchyma, targeting both the central and the peripheral nervous system in a global pattern...
August 10, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28877262/the-er-retention-protein-rer1-promotes-alpha-synuclein-degradation-via-the-proteasome
#9
Hyo-Jin Park, Daniel Ryu, Mayur Parmar, Benoit I Giasson, Nikolaus R McFarland
Abnormal accumulation of α-synuclein (αSyn) has been linked to endoplasmic-reticulum (ER) stress, defective intracellular protein/vesicle trafficking, and cytotoxicity. Targeting factors involved in ER-related protein processing and trafficking may, therefore, be a key to modulating αSyn levels and associated toxicity. Recently retention in endoplasmic reticulum 1 (RER1) has been identified as an important ER retrieval/retention factor for Alzheimer's disease proteins and negatively regulates amyloid-β peptide levels...
2017: PloS One
https://www.readbyqxmd.com/read/28871332/rem-sleep-behavior-disorder-autonomic-dysfunction-and-synuclein-related-neurodegeneration-where-do-we-stand
#10
REVIEW
Giacomo Chiaro, Giovanna Calandra-Buonaura, Annagrazia Cecere, Francesco Mignani, Luisa Sambati, Giuseppe Loddo, Pietro Cortelli, Federica Provini
INTRODUCTION: From newfound parasomnia to a marker of future synucleinopathy, since its first description in 1986, REM sleep behavior disorder (RBD) has been systematically tackled from virtually many viewpoints in basic, translational, and clinical studies. The time delay between RBD and synucleinopathy onset offers an exceptional window for observation and design of neuroprotective trials. In the last few years, research has focused on characterizing possible differences within RBD patients in order to draw potential profiles more or less susceptible to further neurodegeneration...
September 4, 2017: Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society
https://www.readbyqxmd.com/read/28870518/multitep-platform-based-dna-vaccines-for-alpha-synucleinopathies-preclinical-evaluation-of-immunogenicity-and-therapeutic-potency
#11
Hayk Davtyan, Karen Zagorski, Irina Petrushina, Konstantin Kazarian, Natalie R S Goldberg, Janet Petrosyan, Mathew Blurton-Jones, Eliezer Masliah, David H Cribbs, Michael G Agadjanyan, Anahit Ghochikyan
We have previously demonstrated that anti-beta amyloid DNA vaccine (AV-1959D) based on our proprietary MultiTEP platform technology is extremely immunogenic in mice, rabbits, and monkeys. Importantly, MultiTEP platform enables development of vaccines targeting pathological molecules involved in various neurodegenerative disorders. Taking advantage of the universality of MultiTEP platform, we developed DNA vaccines targeting 3 B-cell epitopes (amino acids [aa]85-99, aa109-126, and aa126-140) of human alpha-synuclein (hα-Syn) separately or all 3 epitopes simultaneously...
November 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28869766/vaccination-strategies-in-tauopathies-and-synucleinopathies
#12
Anne K Braczynski, Jörg B Schulz, Jan-Philipp Bach
Vaccination therapies constitute potential treatment options in neurodegenerative disorders such as Alzheimer disease or Parkinson disease. While a lot of research has been performed on vaccination against extracellular amyloid β, the focus recently shifted towards vaccination against the intracellular proteins tau and α-synuclein, with promising results in terms of protein accumulation reduction. In the current review, we briefly summarize lessons to be learned from clinical vaccination trials in Alzheimer disease that target amyloid β...
September 4, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28866688/alpha-synuclein-to-the-rescue-immune-cell-recruitment-by-alpha-synuclein-during-gastrointestinal-infection
#13
Viviane Labrie, Patrik Brundin
Intraneuronal accumulation of misfolded alpha-synuclein in the central and peripheral nervous systems is strongly linked to Parkinson disease (PD) and other related synucleinopathies. In rare inherited forms of PD, point mutations or gene multiplications mediate the formation of alpha-synuclein protein aggregates. However, in most PD cases it is presumed that the combined effects of ageing and environmental factors drive the formation of alpha-synuclein aggregates. Despite advances regarding alpha-synuclein pathobiology, the normal functions of this protein and factors that regulate its expression are not well understood...
2017: Journal of Innate Immunity
https://www.readbyqxmd.com/read/28860330/recent-advances-in-neuropathology-biomarkers-and-therapeutic-approach-of-multiple-system-atrophy
#14
REVIEW
Shunsuke Koga, Dennis W Dickson
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterised by a variable combination of autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal symptoms. The pathological hallmark is the oligodendrocytic glial cytoplasmic inclusion (GCI) consisting of α-synuclein; therefore, MSA is included in the category of α-synucleinopathies. MSA has been divided into two clinicopathological subtypes: MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia, which generally correlate with striatonigral degeneration and olivopontocerebellar atrophy, respectively...
August 31, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/28859333/%C3%AE-synucleinopathy-in-the-human-amygdala-in-parkinson-disease-differential-vulnerability-of-somatostatin-and-parvalbumin-expressing-neurons
#15
Alicia Flores-Cuadrado, Isabel Ubeda-Bañon, Daniel Saiz-Sanchez, Alino Martinez-Marcos
Olfactory dysfunction and emotional impairment are nonmotor symptoms in Parkinson disease (PD). These symptoms might be correlated with the appearance of Lewy bodies and neurites (ubiquitin and α-synuclein aggregates) in the amygdala (Braak stage 3). α-Synucleinopathy in the amygdala has been studied only occasionally, and no data on cell types involved are available. This work aimed to analyze α-synuclein expression in the basolateral, central, and cortical amygdaloid nuclei in 5 PD patients (Braak stages 3-5) and 5 controls...
September 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28855681/%C3%AE-synuclein-amyloids-hijack-prion-protein-to-gain-cell-entry-facilitate-cell-to-cell-spreading-and-block-prion-replication
#16
Suzana Aulić, Lara Masperone, Joanna Narkiewicz, Elisa Isopi, Edoardo Bistaffa, Elena Ambrosetti, Beatrice Pastore, Elena De Cecco, Denis Scaini, Paola Zago, Fabio Moda, Fabrizio Tagliavini, Giuseppe Legname
The precise molecular mechanism of how misfolded α-synuclein (α-Syn) accumulates and spreads in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrP(C)) in mediating the uptake and the spread of recombinant α-Syn amyloids. The in vitro data revealed that the presence of PrP(C) fosters the higher uptake of α-Syn amyloid fibrils, which was also confirmed in vivo in wild type (Prnp (+/+)) compared to PrP knock-out (Prnp (-/-)) mice. Additionally, the presence of α-Syn amyloids blocked the replication of scrapie prions (PrP(Sc)) in vitro and ex vivo, indicating a link between the two proteins...
August 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28843020/clinicopathologic-discrepancies-in-a-population-based-incidence-study-of-parkinsonism-in-olmsted-county-1991-2010
#17
Pierpaolo Turcano, Michelle M Mielke, Keith A Josephs, James H Bower, Joseph E Parisi, Bradley F Boeve, Rodolfo Savica
OBJECTIVE: The purpose of this study was to examine the discrepancies between the clinical diagnosis of parkinsonism and neuropathological findings in a population-based cohort with parkinsonian disorders. BACKGROUND: The specific clinical diagnosis of parkinsonism is challenging, and definite confirmation requires neuropathological evaluation. Currently, autopsies are seldom performed, and most brain autopsies represent atypical or diagnostically unresolved cases...
August 26, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28834018/gba-mutations-in-parkinson-disease-earlier-death-but-similar-neuropathological-features
#18
C H Adler, T G Beach, H A Shill, J N Caviness, E Driver-Dunckley, M N Sabbagh, A Patel, L I Sue, G Serrano, S A Jacobson, K Davis, C M Belden, B N Dugger, S A Paciga, A R Winslow, W D Hirst, J G Hentz
BACKGROUND AND PURPOSE: Mutations in the glucocerebrosidase (GBA) gene are known to be a risk factor for Parkinson's disease (PD). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene. METHODS: Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to identify autopsied PD cases that did or did not have a GBA gene mutation...
August 17, 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/28833467/dopamine-transporter-imaging-deficit-predicts-early-transition-to-synucleinopathy-in-idiopathic-rem-sleep-behavior-disorder
#19
Alex Iranzo, Joan Santamaría, Francesc Valldeoriola, Monica Serradell, Manel Salamero, Carles Gaig, Aida Niñerola-Baizan, Raquel Sánchez-Valle, Albert Lladó, Roberto De Marzi, Ambra Stefani, Klaus Seppi, Javier Pavia, Birgit Högl, Werner Poewe, Eduard Tolosa, Francesc Lomeña
OBJECTIVE: To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic REM sleep behavior disorder (IRBD) patients at risk for short-term development of clinically-defined synucleinopathy. METHODS: Eighty-seven patients with polysomnography-confirmed IRBD underwent (123) I-FP-CIT DAT-SPECT. Results were compared with 20 matched controls without RBD who underwent DAT-SPECT. In patients, FP-CIT uptake was considered abnormal when values were two standard deviations below controls' mean uptake...
August 22, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28828740/the-oligomer-hypothesis-in-%C3%AE-synucleinopathy
#20
REVIEW
Kenjiro Ono
Lewy bodies and Lewy neurites in the brain constitute the main histopathological features of Parkinson's disease (PD) and dementia with Lewy bodies. They comprise amyloid-like fibrils composed of α-synuclein (αS), a small protein (~14 kDa). Because the aggregation of αS in the brain has been implicated as a critical step in the development of these diseases, the research for disease-modifying drugs has focused on modification of the αS aggregation process in the brain. Recent studies using synthetic αS peptides, a cell culture model, transgenic mice models, and human samples such as cerebrospinal fluids and the blood of PD patients have suggested that pre-fibrillar forms of αS (i...
August 21, 2017: Neurochemical Research
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