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synucleinopathy

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https://www.readbyqxmd.com/read/28213435/genetics-of-synucleinopathies
#1
Robert L Nussbaum
Parkinson's disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA) constitute the three major neurodegenerative disorders referred to as synucleinopathies because both genetic and pathological results implicate the α-synuclein protein in their pathogenesis. PD and DLBD are recognized as closely related diseases with substantial clinical and pathological overlap. MSA, on the other hand, has a distinctive clinical presentation and neuropathological profile. In this review, we will summarize the evidence linking α-synuclein to these three disorders...
February 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28202694/pure-autonomic-failure-predictors-of-conversion-to-clinical-cns-involvement
#2
Wolfgang Singer, Sarah E Berini, Paola Sandroni, Robert D Fealey, Elizabeth A Coon, Mariana D Suarez, Eduardo E Benarroch, Phillip A Low
OBJECTIVE: Based on the observation that a subset of patients originally diagnosed with pure autonomic failure (PAF) eventually develops extrapyramidal or cerebellar involvement consistent with multiple system atrophy (MSA), Parkinson disease (PD), or dementia with Lewy bodies (DLB), we aimed to identify predictors of progression of PAF to more sinister synucleinopathies. METHODS: In this retrospective cohort study, we reviewed patients seen at Mayo Clinic Rochester by autonomic specialists between 2001 and 2011 and during initial evaluation diagnosed with orthostatic hypotension consistent with PAF (possible PAF)...
February 15, 2017: Neurology
https://www.readbyqxmd.com/read/28195695/o-glcnacylation-of-%C3%AE-synuclein-at-serine-87-reduces-aggregation-without-affecting-membrane-binding
#3
Yuka E Lewis, Ana Galesic, Paul M Levine, Cesar A De Leon, Natalie Lamiri, Caroline K Brennan, Matthew R Pratt
The aggregation of neurodegenerative-disease associated proteins can be affected by many factors, including a variety of posttranslational modifications. One such modification, O-GlcNAcylation, has been found on some of these aggregation prone proteins, including α-synuclein, the major protein that plays a causative role in synucleinopathies like Parkinson's disease. We previously used synthetic protein chemistry to prepare α-synuclein bearing an homogeneous O-GlcNAc modification at threonine 72 and showed that this modification inhibits protein aggregation...
February 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28188385/pure-autonomic-failure-without-synucleinopathy
#4
Risa Isonaka, Courtney Holmes, Glen A Cook, Patti Sullivan, Yehonatan Sharabi, David S Goldstein
Pure autonomic failure is a rare form of chronic autonomic failure manifesting with neurogenic orthostatic hypotension and evidence of sympathetic noradrenergic denervation unaccompanied by signs of central neurodegeneration. It has been proposed that pure autonomic failure is a Lewy body disease characterized by intra-neuronal deposition of the protein alpha-synuclein in Lewy bodies and neurites. A middle-aged man with previously diagnosed pure autonomic failure experienced a sudden, fatal cardiac arrest. He was autopsied, and tissues were harvested for neurochemical and immunofluorescence studies...
February 10, 2017: Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society
https://www.readbyqxmd.com/read/28180961/dermal-phospho-alpha-synuclein-deposits-confirm-rem-sleep-behaviour-disorder-as-prodromal-parkinson-s-disease
#5
Kathrin Doppler, Hanna-Maria Jentschke, Lena Schulmeyer, David Vadasz, Annette Janzen, Markus Luster, Helmut Höffken, Geert Mayer, Joachim Brumberg, Jan Booij, Thomas Musacchio, Stephan Klebe, Elisabeth Sittig-Wiegand, Jens Volkmann, Claudia Sommer, Wolfgang H Oertel
Phosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson's disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in patients with a high risk of developing PD, such as those with REM sleep behaviour disorder (RBD). We compared the presence and distribution of p-alpha-syn deposits in dermal nerve fibres in 18 patients with RBD, 25 patients with early PD and 20 normal controls...
February 8, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28170377/%C3%AE-synuclein-toxicity-in-neurodegeneration-mechanism-and-therapeutic-strategies
#6
REVIEW
Yvette C Wong, Dimitri Krainc
Alterations in α-synuclein dosage lead to familial Parkinson's disease (PD), and its accumulation results in synucleinopathies that include PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Furthermore, α-synuclein contributes to the fibrilization of amyloid-b and tau, two key proteins in Alzheimer's disease, which suggests a central role for α-synuclein toxicity in neurodegeneration. Recent studies of factors contributing to α-synuclein toxicity and its disruption of downstream cellular pathways have expanded our understanding of disease pathogenesis in synucleinopathies...
February 7, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28159635/%C3%AE-synuclein-binds-to-cytoplasmic-vesicles-in-u251-glioblastoma-cells
#7
Jinyan Duan, Zhengxin Ying, Yang Su, Fankai Lin, Yulin Deng
α-Synuclein is the major component of Lewy bodies, Lewy neurites, and glial cytoplasmic inclusions. It plays an important role in neurodegenerative diseases such as Parkinson's disease, multiple system atrophy, and other synucleinopathies. However, the pathogenesis and neurodegenerative effects of α-synuclein remain unknown. In this study, we established an α-synuclein and an α-synuclein-EGFP overexpressing U251 cell line. α-Synuclein overexpression increases oxidative stress and alters the cell surface and mitochondrial morphologies...
January 31, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28155912/repurposing-doxycycline-for-synucleinopathies-remodelling-of-%C3%AE-synuclein-oligomers-towards-non-toxic-parallel-beta-sheet-structured-species
#8
Florencia González-Lizárraga, Sergio B Socías, César L Ávila, Clarisa M Torres-Bugeau, Leandro R S Barbosa, Andres Binolfi, Julia E Sepúlveda-Díaz, Elaine Del-Bel, Claudio O Fernandez, Dulce Papy-Garcia, Rosangela Itri, Rita Raisman-Vozari, Rosana N Chehín
Synucleinophaties are progressive neurodegenerative disorders with no cure to date. An attractive strategy to tackle this problem is repurposing already tested safe drugs against novel targets. In this way, doxycycline prevents neurodegeneration in Parkinson models by modulating neuroinflammation. However, anti-inflammatory therapy per se is insufficient to account for neuroprotection. Herein we characterise novel targets of doxycycline describing the structural background supporting its effectiveness as a neuroprotector at subantibiotic doses...
February 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28148299/propagation-of-pathological-%C3%AE-synuclein-in-marmoset-brain
#9
Aki Shimozawa, Maiko Ono, Daisuke Takahara, Airi Tarutani, Sei Imura, Masami Masuda-Suzukake, Makoto Higuchi, Kazuhiko Yanai, Shin-Ichi Hisanaga, Masato Hasegawa
α-Synuclein is a defining, key component of Lewy bodies and Lewy neurites in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as glial cytoplasmic inclusions in multiple system atrophy (MSA). The distribution and spreading of these pathologies are closely correlated with disease progression. Recent studies have revealed that intracerebral injection of synthetic α-synuclein fibrils or pathological α-synuclein prepared from DLB or MSA brains into wild-type or transgenic animal brains induced prion-like propagation of phosphorylated α-synuclein pathology...
February 2, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28144037/automated-analysis-of-connected-speech-reveals-early-biomarkers-of-parkinson-s-disease-in-patients-with-rapid-eye-movement-sleep-behaviour-disorder
#10
Jan Hlavnička, Roman Čmejla, Tereza Tykalová, Karel Šonka, Evžen Růžička, Jan Rusz
For generations, the evaluation of speech abnormalities in neurodegenerative disorders such as Parkinson's disease (PD) has been limited to perceptual tests or user-controlled laboratory analysis based upon rather small samples of human vocalizations. Our study introduces a fully automated method that yields significant features related to respiratory deficits, dysphonia, imprecise articulation and dysrhythmia from acoustic microphone data of natural connected speech for predicting early and distinctive patterns of neurodegeneration...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28143405/early-start-of-progressive-motor-deficits-in-line-61-%C3%AE-synuclein-transgenic-mice
#11
R Rabl, C Breitschaedel, S Flunkert, S Duller, D Amschl, J Neddens, V Niederkofler, E Rockenstein, E Masliah, H Roemer, B Hutter-Paier
BACKGROUND: Synucleinopathies such as Parkinson's disease or multiple system atrophy are characterized by Lewy bodies in distinct brain areas. These aggregates are mainly formed by α-synuclein inclusions, a protein crucial for synaptic functions in the healthy brain. Transgenic animal models of synucleinopathies are frequently based on over-expression of human wild type or mutated α-synuclein under the regulatory control of different promoters. A promising model is the Line 61 α-synuclein transgenic mouse that expresses the transgene under control of the Thy-1 promoter...
January 31, 2017: BMC Neuroscience
https://www.readbyqxmd.com/read/28133550/the-contribution-of-%C3%AE-synuclein-spreading-to-parkinson-s-disease-synaptopathy
#12
REVIEW
Francesca Longhena, Gaia Faustini, Cristina Missale, Marina Pizzi, PierFranco Spano, Arianna Bellucci
Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson's disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related to α-synuclein deposition at synaptic sites. Indeed, α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28132976/diagnosis-disease-notification-and-management-of-rapid-eye-movement-rem-sleep-behavior-disorder
#13
Takayoshi Shimohata, Yuichi Inoue, Koichi Hirata
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment behavior during REM sleep. It has been demonstrated that patients with idiopathic RBD are at a significantly increased risk of developing one of the α-synucleinopathies later in life, and this is called "phenoconversion". Although some physicians argue against disclosing information that could cause patients psychological stress, the patients also have a "right to know" about their own disease. Therefore, determining when and how to disclose this information, in addition to appropriate follow-up, is important...
January 28, 2017: Rinshō Shinkeigaku, Clinical Neurology
https://www.readbyqxmd.com/read/28131823/in-situ-peroxidase-labeling-and-mass-spectrometry-connects-alpha-synuclein-directly-to-endocytic-trafficking-and-mrna-metabolism-in-neurons
#14
Chee Yeun Chung, Vikram Khurana, Song Yi, Nidhi Sahni, Ken H Loh, Pavan K Auluck, Valeriya Baru, Namrata D Udeshi, Yelena Freyzon, Steven A Carr, David E Hill, Marc Vidal, Alice Y Ting, Susan Lindquist
Synucleinopathies, including Parkinson's disease (PD), are associated with the misfolding and mistrafficking of alpha-synuclein (α-syn). Here, using an ascorbate peroxidase (APEX)-based labeling method combined with mass spectrometry, we defined a network of proteins in the immediate vicinity of α-syn in living neurons to shed light on α-syn function. This approach identified 225 proteins, including synaptic proteins, proteins involved in endocytic vesicle trafficking, the retromer complex, phosphatases and mRNA binding proteins...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28127516/serum-uric-acid-levels-in-parkinson-s-disease-and-related-disorders
#15
Hideki Sakuta, Keisuke Suzuki, Tomoyuki Miyamoto, Masayuki Miyamoto, Ayaka Numao, Hiroaki Fujita, Yuji Watanabe, Koichi Hirata
OBJECTIVE: Serum uric acid (UA) levels are reported to be decreased in patients with Parkinson's disease (PD) and multiple system atrophy (MSA). However, clinical correlates of serum UA levels are still unclear in PD-related disorders. We conducted a cross-sectional study to evaluate the associations between serum UA levels and disease duration, disease severity, and motor function among PD, MSA, and progressive supranuclear palsy (PSP) patients. METHODS: A total of 100 patients with PD, 42 patients with MSA, 30 patients with PSP, and 100 controls were included in this study...
January 2017: Brain and Behavior
https://www.readbyqxmd.com/read/28117497/stimulation-of-synaptoneurosome-glutamate-release-by-monomeric-and-fibrillated-%C3%AE-synuclein
#16
Theodore A Sarafian, Kaitlyn Littlejohn, Sarah Yuan, Charlene Fernandez, Marianne Cilluffo, Bon-Kyung Koo, Julian P Whitelegge, Joseph B Watson
The α-synuclein protein exists in vivo in a variety of covalently modified and aggregated forms associated with Parkinson's disease (PD) pathology. However, the specific proteoform structures involved with neuropathological disease mechanisms are not clearly defined. Since α-synuclein plays a role in presynaptic neurotransmitter release, an in vitro enzyme-based assay was developed to measure glutamate release from mouse forebrain synaptoneurosomes (SNs) enriched in synaptic endings. Glutamate measurements utilizing SNs from various mouse genotypes (WT, over-expressers, knock-outs) suggested a concentration dependence of α-synuclein on calcium/depolarization-dependent presynaptic glutamate release from forebrain terminals...
January 24, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28108534/cell-biology-and-pathophysiology-of-%C3%AE-synuclein
#17
Jacqueline Burré, Manu Sharma, Thomas C Südhof
α-Synuclein is an abundant neuronal protein that is highly enriched in presynaptic nerve terminals. Genetics and neuropathology studies link α-synuclein to Parkinson's disease (PD) and other neurodegenerative disorders. Accumulation of misfolded oligomers and larger aggregates of α-synuclein defines multiple neurodegenerative diseases called synucleinopathies, but the mechanisms by which α-synuclein acts in neurodegeneration are unknown. Moreover, the normal cellular function of α-synuclein remains debated...
January 20, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28096359/%C3%AE-synuclein-binds-and-sequesters-pike-l-into-lewy-bodies-triggering-dopaminergic-cell-death-via-ampk-hyperactivation
#18
Seong Su Kang, Zhentao Zhang, Xia Liu, Fredric P Manfredsson, Li He, P Michael Iuvone, Xuebing Cao, Yi E Sun, Lingjing Jin, Keqiang Ye
The abnormal aggregation of fibrillar α-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating α-synuclein pathological effects are incompletely understood. Here we show that α-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. α-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28093795/the-natural-history-of-pure-autonomic-failure-a-u-s-prospective-cohort
#19
Horacio Kaufmann, Lucy Norcliffe-Kaufmann, Jose-Alberto Palma, Italo Biaggioni, Phillip A Low, Wolfgang Singer, David S Goldstein, Amanda C Peltier, Cyndia A Shibao, Christopher H Gibbons, Roy Freeman, David Robertson
OBJECTIVE: To define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. METHODS: One hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the U.S. Seventy-four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests...
January 17, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28087304/sleep-and-neurodegeneration-a-critical-appraisal
#20
REVIEW
Jagan A Pillai, James B Leverenz
Sleep abnormalities are clearly recognized as distinct clinical symptom of concern in neurodegenerative disorders. Appropriate management of sleep related symptoms has a positive impact on the quality of life of patients with neurodegenerative disorders. This review provides an overview of mechanisms that are currently being considered that tie sleep with neurodegeneration. It appraises the literature regarding specific sleep changes among common neurodegenerative diseases with a focus on Alzheimer's disease and synucleinopathies (i...
January 10, 2017: Chest
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