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Alpha-synuclein

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https://www.readbyqxmd.com/read/27911008/comparison-of-neuropathology-in-parkinson-s-disease-subjects-with-and-without-deep-brain-stimulation
#1
Gian D Pal, Bichun Ouyang, Geidy Serrano, Holly A Shill, Christopher Goetz, Glenn Stebbins, Leo Verhagen Metman, Erika Driver-Dunckley, Shyamal H Mehta, John N Caviness, Marwan N Sabbagh, Charles H Adler, Thomas G Beach
BACKGROUND: The aim of this postmortem study was to compare, in Parkinson's disease subjects with and without bilateral subthalamic nucleus deep brain stimulation (STN-DBS), the loss of pigmented neurons within the substantia nigra and pathological alpha-synuclein density within the SN and other brain regions. METHODS: PD subjects were identified from the Arizona Study of Aging and Neurodegenerative Disorders database (STN-DBS = 11, non-DBS = 156). Pigmented neuron loss scores within the substantia nigra as well as alpha-synuclein density scores within the substantia nigra and 9 other brain regions were compared, the latter individually and in summary as the Lewy body brain load score...
December 2, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27904950/age-dependent-alpha-synuclein-accumulation-is-correlated-with-elevation-of-mitochondrial-trpc3-in-the-brains-of-monkeys-and-mice
#2
Min Chen, Jia Liu, Yongquan Lu, Chunli Duan, Lingling Lu, Ge Gao, Piu Chan, Shun Yu, Hui Yang
Aberrant α-synuclein (α-syn) accumulation has been shown to impair mitochondrial function by reducing mitochondrial membrane potential (MMP). However, the underlying mechanisms remain elusive. Transient receptor potential canonical (TRPC) channels are a diverse group of non-selective Ca(2+) channels, among which TRPC3 is the only one that is localized in mitochondria and plays a role in maintaining the normal MMP. This raises a possibility that altered TRPC3 expression may play a role in the mitochondrial dysfunction induced by α-syn accumulation...
November 30, 2016: Journal of Neural Transmission
https://www.readbyqxmd.com/read/27904575/alpha-synuclein-structure-functions-and-interactions
#3
REVIEW
Fatemeh Nouri Emamzadeh
At present, when a clinical diagnosis of Parkinson's disease (PD) is made, serious damage has already been done to nerve cells of the substantia nigra pars compacta. The diagnosis of PD in its earlier stages, before this irreversible damage, would be of enormous benefit for future treatment strategies designed to slow or halt the progression of this disease that possibly prevents accumulation of toxic aggregates. As a molecular biomarker for the detection of PD in its earlier stages, alpha-synuclein (α-syn), which is a key component of Lewy bodies, in which it is found in an aggregated and fibrillar form, has attracted considerable attention...
2016: Journal of Research in Medical Sciences: the Official Journal of Isfahan University of Medical Sciences
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
#4
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/27901068/nanomechanical-properties-of-distinct-fibrillar-polymorphs-of-the-protein-%C3%AE-synuclein
#5
Ali Makky, Luc Bousset, Jérôme Polesel-Maris, Ronald Melki
Alpha-synuclein (α-Syn) is a small presynaptic protein of 140 amino acids. Its pathologic intracellular aggregation within the central nervous system yields protein fibrillar inclusions named Lewy bodies that are the hallmarks of Parkinson's disease (PD). In solution, pure α-Syn adopts an intrinsically disordered structure and assembles into fibrils that exhibit considerable morphological heterogeneity depending on their assembly conditions. We recently established tightly controlled experimental conditions allowing the assembly of α-Syn into highly homogeneous and pure polymorphs...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27900791/robust-graft-survival-and-normalized-dopaminergic-innervation-does-not-obligate-recovery-in-a-pd-patient
#6
Jeffrey H Kordower, Christopher G Goetz, Yaping Chu, Glenda M Halliday, Daniel A Nicholson, Timothy Musial, David J Marmion, A Jon Stoessl, Vesna Sossi, Thomas B Freeman, C Warren Olanow
OBJECTIVE: The main goal of dopamine cell replacement therapy in Parkinson's disease (PD) is to provide clinical benefit mediated by graft survival with nigrostriatal reinnervation. We report a dichotomy between graft structure and clinical function in a patient dying sixteen years following fetal nigral grafting. METHODS: A 55-year-old levodopa-responsive woman with PD received bilateral putamenal fetal mesencephalic grafts as part of an NIH-sponsored double-blind sham-controlled trial...
November 30, 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27896833/exploiting-the-aggregation-properties-of-alpha-synuclein-for-diagnostic-purposes
#7
David P Breen, Lorraine V Kalia
No abstract text is available yet for this article.
November 29, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
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
#8
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/27895530/alpha-synuclein-contributes-to-malignant-progression-of-human-meningioma-via-the-akt-mtor-pathway
#9
Yiqin Ge, Kan Xu
BACKGROUND: The aim of this study is to explore the expression of alpha-synuclein (α-synuclein) in benign, atypical, and anaplastic meningiomas and determine its role in the malignant progression of meningiomas. METHODS: Expression of α-synuclein was measured in 44 meningioma samples by real-time PCR analysis. The effects of overexpression or knockdown of α-synuclein on meningioma cell growth, invasiveness, and tumorigenicity were determined. RESULTS: Atypical and anaplastic meningiomas displayed significantly greater levels of α-synuclein mRNA, relative to benign tumors...
2016: Cancer Cell International
https://www.readbyqxmd.com/read/27893183/toxic-effects-of-human-and-rodent-variants-of-alpha-synuclein-in-vivo
#10
Natalie Landeck, Kerstin Buck, Deniz Kirik
In Parkinson's disease, abnormal alpha-synuclein (asyn) accumulation leads to the formation of soluble oligomeric species thought to be toxic to cells as well as intraneuronal inclusions. To date, the precise mechanisms leading to aggregation of asyn in the brain is not well understood. Previous studies in yeast, drosophila and transgenic mice suggested that a non-A beta component depleted version of human asyn [h-asyn(D70-83)] or human beta-synuclein (h-bsyn), naturally lacking this centrally located hydrophobic region, are less prone to form aggregates in vitro and are expected to be less toxic compared to h-asyn in vivo, although not all experimental studies unequivocally support the latter view...
November 28, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27890431/neuroprotective-mechanisms-of-plant-extracts-against-mptp-induced-neurotoxicity-future-applications-in-parkinson-s-disease
#11
REVIEW
Abdelrahman Ibrahim Abushouk, Ahmed Negida, Hussien Ahmed, Mohamed M Abdel-Daim
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, affecting about seven to 10 million patients worldwide. The major pathological features of PD are loss of dopaminergic neurons in the nigrostriatal pathway and accumulation of alpha-synuclein molecules, forming Lewy bodies. Until now, there is no effective cure for PD, and investigators are searching for neuroprotective strategies to stop or slow the disease progression. The MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced neurotoxicity of the nigrostriatal pathway has been used to initiate PD in animal models...
November 24, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27888296/toll-like-receptor-2-is-increased-in-neurons-in-parkinson-s-disease-brain-and-may-contribute-to-alpha-synuclein-pathology
#12
Nicolas Dzamko, Amanda Gysbers, Gayathri Perera, Anita Bahar, Amrita Shankar, Jianqun Gao, YuHong Fu, Glenda M Halliday
Inflammation is likely a key contributor to the pathogenesis of Parkinson's disease (PD), a progressively debilitating neurodegenerative disease that is accompanied by a pathological accumulation of the α-synuclein protein in a staged manner through the brain. What leads to the accumulation of α-synuclein in PD and how this relates to inflammatory pathways, however, is not entirely clear. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation and, in particular, TLR2 is increasingly being implicated in PD...
November 25, 2016: Acta Neuropathologica
https://www.readbyqxmd.com/read/27873359/constipation-in-parkinson-s-disease-subjective-symptoms-objective-markers-and-new-perspectives
#13
REVIEW
Karoline Knudsen, Klaus Krogh, Karen Østergaard, Per Borghammer
Constipation is among the first nonmotor symptoms to develop in the prodromal phase of PD. Pathological alpha-synuclein deposition is present throughout the gastrointestinal tract up to 20 years preceding diagnosis. Nevertheless, constipation in the context of PD remains ill defined and poorly understood. In this review, we summarize current knowledge of subjective symptoms and objective measures of constipation in PD. More than 10 different definitions of constipation have been used in the PD literature, making generalizations difficult...
November 22, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27872751/novel-gene-tmem230-linked-to-parkinson-s-disease
#14
EDITORIAL
Diana A Olszewska, Conor Fearon, Tim Lynch
Mutations in six genes are known to cause Parkinson's disease (PD) (autosomal dominant: alpha-synuclein, LRRK2, VPS35 and autosomal recessive: Parkin, PINK1 and DJ1) and number of other genes are implicated. In a recent article Deng and colleagues studied a large four generation American family of European descent and linked mutations in a novel gene, transmembrane-protein 230 gene (TMEM230) with lewy body confirmed PD. The authors demonstrated that pathogenic TMEM230 variants in primary mouse neurons affected movement of synaptic vesicles suggesting that TMEM230 may slow vesicular transport...
2016: Journal of Clinical Movement Disorders
https://www.readbyqxmd.com/read/27871937/elevated-levels-of-alpha-synuclein-blunt-cellular-signal-transduction-downstream-of-gq-protein-coupled-receptors
#15
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/27863657/development-and-characterization-of-polo-like-kinase-2-loaded-nanoparticles-a-novel-strategy-for-serine-129-phosphorylation-of-alpha-synuclein
#16
C Rodríguez-Nogales, E Garbayo, I Martínez-Valbuena, V Sebastián, M R Luquin, M J Blanco-Prieto
Polo like kinase 2 (PLK2), a serine/threonine serum inducible kinase, has been proposed to be the major factor responsible for phosphorylating alpha-synuclein (α-syn) at Serine-129 (Ser-129) in Parkinson's disease (PD). A suitable strategy to gain insights into PLK2's biological effects might be to increase PLK2 intracellular levels with the aim of reproducing the slow progressive neuronal changes that occur in PD. The goal of this study was to develop and characterize a novel drug delivery system (DDS) for PLK2 cytosolic delivery using Total recirculating one machine system (TROMS), a technique capable of encapsulating fragile molecules while maintaining their native properties...
November 30, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27862327/an-order-in-lewy-body-disorders-retrograde-degeneration-in-hyperbranching-axons-as-a-fundamental-structural-template-accounting-for-focal-multifocal-lewy-body-disease
#17
REVIEW
Toshiki Uchihara 内原 俊記
Initial clinical recognition of "paralysis agitans" by James Parkinson was expanded by Jean-Martin Charcot, who recognized additional clinical findings of his own, such as slowness (distinct from paralysis), rigidity (distinct from spasticity) and characteristic countenance. Charcot assembled these findings under the umbrella of "Parkinson disease (PD)". This purely clinical concept was so prescient and penetrating that subsequent neuropathological and biochemical evidences were ordered along this axis to establish the nigra-central trinity of PD (dopamine depletion, nigral lesion with Lewy bodies: LBs)...
November 14, 2016: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/27861638/propagated-but-topologically-distributed-forebrain-neurons-expressing-alpha-synuclein-in-aged-macaques
#18
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/27853754/commentary-alpha-synuclein-interacts-with-sod1-and-promotes-its-oligomerization
#19
Anika M Helferich, Pamela J McLean, Jochen H Weishaupt, Karin M Danzer
Alpha-synuclein and Cu, Zn superoxide dismutase (SOD1) are both aggregation-prone proteins that are associated with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), respectively. Recently, we showed that alpha-synuclein interacts with SOD1 in various cell types and tissues. Using a cell culture model, we also found that alpha-synuclein nucleates the polymerization of SOD1. Here, we discuss the current literature regarding their interaction and their co-localization in aggregates of human post-mortem tissue...
2016: Journal of Neurology & Neuromedicine
https://www.readbyqxmd.com/read/27853185/phosphorylation-induces-distinct-alpha-synuclein-strain-formation
#20
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
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