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https://www.readbyqxmd.com/read/27920026/the-transcellular-propagation-and-intracellular-trafficking-of-%C3%AE-synuclein
#1
George K Tofaris, Michel Goedert, Maria Grazia Spillantini
Parkinson's disease is the second most common neurodegenerative disorder, with only partial symptomatic therapy and no mechanism-based therapies. The accumulation and aggregation of α-synuclein is causatively linked to the sporadic form of the disease, which accounts for 95% of cases. The pathology is a result of a gain of toxic function of misfolded α-synuclein conformers, which can template the aggregation of soluble monomers and lead to cellular dysfunction, at least partly by interfering with membrane fusion events at synaptic terminals...
December 5, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27918765/development-of-a-biochemical-diagnosis-of-parkinson-disease-by-detection-of-%C3%AE-synuclein-misfolded-aggregates-in-cerebrospinal-fluid
#2
Mohammad Shahnawaz, Takahiko Tokuda, Masaaki Waragai, Nicolas Mendez, Ryotaro Ishii, Claudia Trenkwalder, Brit Mollenhauer, Claudio Soto
Importance: Parkinson disease (PD) is a highly prevalent and incurable neurodegenerative disease associated with the accumulation of misfolded α-synuclein (αSyn) aggregates. An important problem in this disease is the lack of a sensitive, specific, and noninvasive biochemical diagnosis to help in clinical evaluation, monitoring of disease progression, and early differential diagnosis from related neurodegenerative diseases. Objective: To develop a novel assay with high sensitivity and specificity to detect small quantities of αSyn aggregates circulating in cerebrospinal fluid (CSF) of patients affected by PD and related synucleinopathies...
December 5, 2016: JAMA Neurology
https://www.readbyqxmd.com/read/27917933/inhibition-of-alpha-synuclein-aggregation-by-multifunctional-dopamine-agonists-assessed-by-a-novel-in-vitro-assay-and-an-in-vivo-drosophila-synucleinopathy-model
#3
Deepthi Yedlapudi, Gnanada S Joshi, Dan Luo, Sokol V Todi, Aloke K Dutta
Aggregation of alpha synuclein (α-syn) leading to dopaminergic neuronal death has been recognized as one of the main pathogenic factors in the initiation and progression of Parkinson's disease (PD). Consequently, α-syn has been targeted for the development of therapeutics for PD. We have developed a novel assay to screen compounds with α-syn modulating properties by mimicking recent findings from in vivo animal studies involving intrastriatal administration of pre-formed fibrils in mice, resulting in increased α-syn pathology accompanying the formation of Lewy-body (LB) type inclusions...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27912057/gut-microbiota-regulate-motor-deficits-and-neuroinflammation-in-a-model-of-parkinson-s-disease
#4
Timothy R Sampson, Justine W Debelius, Taren Thron, Stefan Janssen, Gauri G Shastri, Zehra Esra Ilhan, Collin Challis, Catherine E Schretter, Sandra Rocha, Viviana Gradinaru, Marie-Francoise Chesselet, Ali Keshavarzian, Kathleen M Shannon, Rosa Krajmalnik-Brown, Pernilla Wittung-Stafshede, Rob Knight, Sarkis K Mazmanian
The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27902767/towards-a-non-human-primate-model-of-alpha-synucleinopathy-for-development-of-therapeutics-for-parkinson-s-disease-optimization-of-aav1-2-delivery-parameters-to-drive-sustained-expression-of-alpha-synuclein-and-dopaminergic-degeneration-in-macaque
#5
James B Koprich, Tom H Johnston, Gabriela Reyes, Vanessa Omana, Jonathan M Brotchie
Recent failures in clinical trials for disease modification in Parkinson's disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway...
2016: PloS One
https://www.readbyqxmd.com/read/27898200/transcranial-sonography-in-idiopathic-rem-sleep-behavior-disorder-and-multiple-system-atrophy
#6
Xudong Li, Shuang Xue, Shuhong Jia, Zhi Zhou, Yanan Qiao, Chunlei Hou, Kun Wei, Wenjing Zheng, Pei Rong, Jinsong Jiao
AIMS: We investigated preclinical abnormalities revealed by transcranial sonography (TCS) in patients with idiopathic REM sleep behavior disorder (iRBD) compared with those revealed in patients with multiple system atrophy (MSA) or Parkinson's disease (PD) and in normal controls. METHODS: Twenty-two patients with iRBD, 21 patients with MSA, 22 patients with PD and 21 normal controls were included in this study. All participants underwent one night of video-polysomnography (PSG) monitoring, and the sleep parameters were analyzed using Polysmith software and by visual analysis...
November 29, 2016: Psychiatry and Clinical Neurosciences
https://www.readbyqxmd.com/read/27895548/a-novel-microfluidic-cell-co-culture-platform-for-the-study-of-the-molecular-mechanisms-of-parkinson-s-disease-and-other-synucleinopathies
#7
João T S Fernandes, Oldriska Chutna, Virginia Chu, João P Conde, Tiago F Outeiro
Although, the precise molecular mechanisms underlying Parkinson's disease (PD) are still elusive, it is now known that spreading of alpha-synuclein (aSyn) pathology and neuroinflammation are important players in disease progression. Here, we developed a novel microfluidic cell-culture platform for studying the communication between two different cell populations, a process of critical importance not only in PD but also in many biological processes. The integration of micro-valves in the device enabled us to control fluid routing, cellular microenvironments, and to simulate paracrine signaling...
2016: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/27875637/ambra1-a-novel-%C3%AE-synuclein-binding-protein-is-implicated-in-the-pathogenesis-of-multiple-system-atrophy
#8
Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Yota Tatara, Jun Utsumi, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Gian Maria Fimia, Koichi Wakabayashi
The accumulation of abnormal α-synuclein is the major histopathological feature of Lewy body disease and multiple system atrophy (MSA), which are referred to as synucleinopathies. Although the pathomechanisms underlying synucleinopathies are still unknown, mounting evidence indicates that cytoplasmic degradation systems, such as the autophagy-lysosome and proteasome pathways, are strongly involved in their pathogenesis. Autophagy is tightly regulated by several upstream proteins including UNC-51-like kinase 1/2, beclin1, vacuolar protein sorting-associated protein 34, and autophagy/beclin1 regulator 1 (AMBRA1)...
November 22, 2016: Brain Pathology
https://www.readbyqxmd.com/read/27871937/elevated-levels-of-alpha-synuclein-blunt-cellular-signal-transduction-downstream-of-gq-protein-coupled-receptors
#9
Mattia Volta, Alexandros A Lavdas, Julia Obergasteiger, Christa Überbacher, Anne Picard, Peter P Pramstaller, Andrew A Hicks, Corrado Corti
Alpha-synuclein is central to Parkinson's disease pathogenesis and pathology, however its precise functions are still unclear. It has been shown to bind both PLCβ1 and MAPKs, but how this property influences the downstream signaling of Gq protein-coupled receptors has not been elucidated. Here we show that recombinant expression of alpha-synuclein in human neuroblastoma cells enhances cellular levels of PLCβ1 but blunts its signaling pathway, preventing the agonist-dependent rise of cytoplasmic Ca(2+). In addition, overexpressing alpha-synuclein abolishes the activation of ERK1/2 upon agonist stimulation, indicating an upstream action in the signal transduction pathway...
November 18, 2016: Cellular Signalling
https://www.readbyqxmd.com/read/27869325/a-novel-therapeutic-approach-for-synucleinopathies
#10
Roberto Erro
No abstract text is available yet for this article.
November 21, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27863716/antibodies-against-the-c-terminus-of-%C3%AE-synuclein-modulate-its-fibrillation
#11
Cagla Sahin, Nikolai Lorenzen, Lasse Lemminger, Gunna Christiansen, Ian Max Møller, Louise Buur Vesterager, Lars Østergaard Pedersen, Karina Fog, Pekka Kallunki, Daniel E Otzen
The 140-residue natively disordered protein α-synuclein (aSN) is a central component in the development of a family of neurodegenerative diseases termed synucleinopathies. This is attributed to its ability to form cytotoxic aggregates such as oligomers and amyloid fibrils. Consequently there have been intense efforts to avoid aggregation or reroute the aggregation pathway using pharmaceutical agents such as small molecules, chaperones and antibodies. aSN's lack of persistent structure in the monomeric state, as well as the multitude of different oligomeric and even different fibrillar states, makes it difficult to raise antibodies that would be efficacious in neutralizing all conformations of aSN...
January 2017: Biophysical Chemistry
https://www.readbyqxmd.com/read/27862335/increased-aneuploidy-is-not-a-universal-feature-across-%C3%AE-synucleinopathies
#12
Yue Yang, Claire E Shepherd, Glenda M Halliday
No abstract text is available yet for this article.
November 10, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27861638/propagated-but-topologically-distributed-forebrain-neurons-expressing-alpha-synuclein-in-aged-macaques
#13
Katsuo Kimura, Ken-Ichi Inoue, Yoshiyuki Kuroiwa, Fumiaki Tanaka, Masahiko Takada
In neurodegenerative disorders, such as Parkinson's disease (PD), alpha-synuclein (α-syn) accumulates to induce cell death and/or form a cytoplasmic inclusion called Lewy body (LB). This α-syn-related pathology is termed synucleinopathy. It remains unclear how α-syn accumulation expands during the progress of synucleinopathy in the human brain. In our study, we investigated the patterns of distribution and propagation of forebrain neurons expressing α-syn in aged macaques. It was found that the occurrence of α-syn-positive neurons proceeded topologically based on the midbrain dopamine pathways arising from the substantia nigra and the ventral tegmental area where they were primarily observed...
2016: PloS One
https://www.readbyqxmd.com/read/27853185/phosphorylation-induces-distinct-alpha-synuclein-strain-formation
#14
Meng-Rong Ma, Zhi-Wen Hu, Yu-Fen Zhao, Yong-Xiang Chen, Yan-Mei Li
Synucleinopathies are a group of neurodegenerative diseases associated with alpha-synuclein (α-Syn) aggregation. Recently, increasing evidence has demonstrated the existence of different structural characteristics or 'strains' of α-Syn, supporting the concept that synucleinopathies share several common features with prion diseases and possibly explaining how a single protein results in different clinical phenotypes within synucleinopathies. In earlier studies, the different strains were generated through the regulation of solution conditions, temperature, or repetitive seeded fibrillization in vitro...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27845893/klk6-proteolysis-is-implicated-in-the-turnover-and-uptake-of-extracellular-alpha-synuclein-species
#15
Georgios Pampalakis, Vasia-Samantha Sykioti, Methodios Ximerakis, Ioanna Stefanakou-Kalakou, Ronald Melki, Kostas Vekrellis, Georgia Sotiropoulou
KLK6 is a serine protease highly expressed in the nervous system. In synucleinopathies, including Parkinson disease, the levels of KLK6 inversely correlate with α-synuclein in CSF. Recently, we suggested that recombinant KLK6 mediates the degradation of extracellular α-synuclein directly and via a proteolytic cascade that involves unidentified metalloproteinase(s). Here, we show that recombinant and naturally secreted KLK6 can readily cleave α-synuclein fibrils that have the potential for cell-to-cell propagation in "a prion-like mechanism"...
November 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27844283/micrornas-in-cerebrospinal-fluid-as-potential-biomarkers-for-parkinson-s-disease-and-multiple-system-atrophy
#16
Tainá M Marques, H Bea Kuiperij, Ilona B Bruinsma, Anouke van Rumund, Marjolein B Aerts, Rianne A J Esselink, Bas R Bloem, Marcel M Verbeek
Parkinson's disease (PD) and multiple system atrophy (MSA) are both part of the spectrum of neurodegenerative movement disorders and α-synucleinopathies with overlap of symptoms especially at early stages of the disease but with distinct disease progression and responses to dopaminergic treatment. Therefore, having biomarkers that specifically classify patients, which could discriminate PD from MSA, would be very useful. MicroRNAs (miRNAs) regulate protein translation and are observed in biological fluids, including cerebrospinal fluid (CSF), and may therefore have potential as biomarkers of disease...
November 14, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27837450/subcellular-parkinson-s-disease-specific-alpha-synuclein-species-show-altered-behavior-in-neurodegeneration
#17
Rashed Abdullah, Ketan S Patil, Benjamin Rosen, Ramavati Pal, Shubhangi Prabhudesai, Sungsu Lee, Indranil Basak, Esthelle Hoedt, Peter Yang, Keith Panick, Hsin-Pin Ho, Emmanuel Chang, Charalampos Tzoulis, Jan Petter Larsen, Thomas A Neubert, Guido Alves, Simon G Møller
Parkinson's disease and other synucleinopathies are characterized by the presence of intra-neuronal protein aggregates enriched in the presynaptic protein α-synuclein. α-synuclein is considered an intrinsically disordered 14 kDa monomer, and although poorly understood, its transition to higher-order multimeric species may play central roles in healthy neurons and during Parkinson's disease pathogenesis. In this study, we demonstrate that α-synuclein exists as defined, subcellular-specific species that change characteristics in response to oxidative stress in neuroblastoma cells and in response to Parkinson's disease pathogenesis in human cerebellum and frontal cortex...
November 11, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27826641/synucleinopathies-common-features-and-hippocampal-manifestations
#18
REVIEW
Weiwei Yang, Shun Yu
Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA) are three major synucleinopathies characterized by α-synuclein-containing inclusions in the brains of patients. Because the cell types and brain structures that are affected vary markedly between the disorders, the patients have different clinical manifestations in addition to some overlapping symptoms, which are the basis for differential diagnosis. Cognitive impairment and depression associated with hippocampal dysfunction are frequently observed in these disorders...
November 8, 2016: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/27824888/bifunctional-anti-non-amyloid-component-%C3%AE-synuclein-nanobodies-are-protective-in-situ
#19
David C Butler, Shubhada N Joshi, Erwin De Genst, Ankit S Baghel, Christopher M Dobson, Anne Messer
Misfolding, abnormal accumulation, and secretion of α-Synuclein (α-Syn) are closely associated with synucleinopathies, including Parkinson's disease (PD). VH14 is a human single domain intrabody selected against the non-amyloid component (NAC) hydrophobic interaction region of α-Syn, which is critical for initial aggregation. Using neuronal cell lines, we show that as a bifunctional nanobody fused to a proteasome targeting signal, VH14PEST can counteract heterologous proteostatic effects of mutant α-Syn on mutant huntingtin Exon1 and protect against α-Syn toxicity using propidium iodide or Annexin V readouts...
2016: PloS One
https://www.readbyqxmd.com/read/27822045/alpha-synuclein-in-cutaneous-small-nerve-fibers
#20
Timo Siepmann, Ben Min-Woo Illigens, Kristian Barlinn
Despite progression in the development of pharmacological therapy, treatment of alpha synucleinopathies, such as Parkinson's disease (PD) and some atypical parkinsonism syndromes, is still challenging. To date, our knowledge of the mechanisms whereby the pathological form of alpha-synuclein causes structural and functional damage to the nervous system is limited and, consequently, there is a lack of specific diagnostic tools to evaluate pathology in these patients and differentiate PD from other neurodegenerative proteinopathies...
2016: Neuropsychiatric Disease and Treatment
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