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Alpha synuclein

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https://www.readbyqxmd.com/read/28526239/cellular-models-as-tools-for-the-study-of-the-role-of-alpha-synuclein-in-parkinson-s-disease
#1
REVIEW
Diana F Lázaro, Maria Angeliki S Pavlou, Tiago Fleming Outeiro
Neurodegenerative diseases are highly debilitating conditions characterised primarily by progressive neuronal loss and impairment of the nervous system. Parkinson's disease (PD) is one of the most common of these disorders, affecting 1-2% of the population above the age of 65. Although the underlying mechanisms of PD have been extensively studied, we still lack a full understanding of the molecular underpinnings of the disease. Thus, the in vitro and in vivo models currently used are able to only partially recapitulate the typical phenotypes of the disease...
May 16, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28520872/glucocerebrosidase-deficiency-in-dopaminergic-neurons-induces-microglial-activation-without-neurodegeneration
#2
Federico N Soria, Michel Engeln, Marta Martinez-Vicente, Christelle Glangetas, María José López-González, Sandra Dovero, Benjamin Dehay, Elisabeth Normand, Miquel Vila, Alexandre Favereaux, François Georges, Christophe Lo Bianco, Erwan Bezard, Pierre-Olivier Fernagut
Mutations in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase (GBA1) are important risk factors for Parkinson's disease (PD). In vitro, altered GBA1 activity promotes alpha-synuclein accumulation while elevated levels of alpha-synuclein compromise GBA1 function, thus supporting a pathogenic mechanism in PD. However, the mechanisms by which GBA1 deficiency is linked to increased risk of PD remains elusive, partially because of lack of aged models of GBA1 deficiency. Since knocking-out GBA1 in the entire brain induces massive neurodegeneration and early death, we generated a mouse model of GBA1 deficiency amenable to investigate the long-term consequences of compromised GBA1 function in dopaminergic neurons...
May 17, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28520803/multiple-modality-biomarker-prediction-of-cognitive-impairment-in-prospectively-followed-de-novo-parkinson-disease
#3
Chelsea Caspell-Garcia, Tanya Simuni, Duygu Tosun-Turgut, I-Wei Wu, Yu Zhang, Mike Nalls, Andrew Singleton, Leslie A Shaw, Ju-Hee Kang, John Q Trojanowski, Andrew Siderowf, Christopher Coffey, Shirley Lasch, Dag Aarsland, David Burn, Lana M Chahine, Alberto J Espay, Eric D Foster, Keith A Hawkins, Irene Litvan, Irene Richard, Daniel Weintraub
OBJECTIVES: To assess the neurobiological substrate of initial cognitive decline in Parkinson's disease (PD) to inform patient management, clinical trial design, and development of treatments. METHODS: We longitudinally assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers. Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta [Aβ], tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition...
2017: PloS One
https://www.readbyqxmd.com/read/28516276/p2x7-receptor-pannexin-1-interaction-mediates-extracellular-alpha-synuclein-induced-atp-release-in-neuroblastoma-sh-sy5y-cells
#4
Anna Wilkaniec, Magdalena Gąssowska, Grzegorz A Czapski, Magdalena Cieślik, Grzegorz Sulkowski, Agata Adamczyk
Abnormalities of alpha-synuclein (ASN), the main component of protein deposits (Lewy bodies), were observed in Parkinson's disease (PD), dementia with Lewy bodies, Alzheimer's disease, and other neurodegenerative disorders. These alterations include increase in the levels of soluble ASN oligomers in the extracellular space. Numerous works have identified several mechanisms of their toxicity, including stimulation of the microglial P2X7 receptor leading to oxidative stress. While the significant role of purinergic signaling-particularly, P2 family receptors-in neurodegenerative disorders is well known, the interaction of extracellular soluble ASN with neuronal purinergic receptors is yet to be studied...
May 17, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/28495859/alpha-synuclein-may-cross-bridge-v-snare-and-acidic-phospholipids-to-facilitate-snare-dependent-vesicle-docking
#5
Xiaochu Lou, Jaewook Kim, Brenden J Hawk, Yeon-Kyun Shin
Misfolded α-synuclein/A-syn is widely recognized as primal cause of neurodegenerative diseases including Parkinson's and dementia with Lewy bodies. The normal cellular function of A-syn has however been elusive. There is evidence that A-syn plays a variety of roles in the exocytotic pathway in the neuron, but the underlying molecular mechanisms are unclear. A-syn has been known to interact with negatively charged phospholipids and with vesicle SNARE protein VAMP2 as well. Using single vesicle-vesicle docking/fusion assays, we find that A-syn promotes SNARE-dependent vesicles docking significantly at 2...
May 11, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28453489/changes-of-cerebrospinal-fluid-peptides-due-to-tauopathy
#6
Petra Majerova, Peter Barath, Alena Michalicova, Stanislav Katina, Michal Novak, Andrej Kovac
Alzheimer's disease (AD) and progressive supranuclear palsy are two common neurodegenerative tauopathies, and the most common cause of progressive brain dementia in elderly affecting more than 35 million people. The tauopathies are characterized by abnormal deposition of microtubule associated protein tau into intracellular neurofibrillary tangles composed mainly of the hyperphosphorylated form of the protein. The diagnosis of tauopathies is based on the presence of clinical features and pathological changes...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28452474/steady-state-kinetics-of-%C3%AE-synuclein-ferrireductase-activity-identifies-the-catalytically-competent-species
#7
Jennifer S McDowall, Ioanna Ntai, Jonathon Hake, Paul R Whitley, Jody M Mason, Christopher R Pudney, David R Brown
α-Synuclein (α-syn) is a cytosolic protein known for its association with neurodegenerative diseases, including Parkinson's disease and other synucleinopathies. The potential cellular function of α-synuclein may be of consequence for understanding the pathogenesis of such diseases. Previous work has suggested that α-synuclein can catalyze the reduction of iron as a ferrireductase. We performed a detailed analysis of the steady-state kinetics of recombinant α-syn ferrireductase activity and for disease-associated variants...
May 4, 2017: Biochemistry
https://www.readbyqxmd.com/read/28450268/extensive-uptake-of-%C3%AE-synuclein-oligomers-in-astrocytes-results-in-sustained-intracellular-deposits-and-mitochondrial-damage
#8
Veronica Lindström, Gabriel Gustafsson, Laurie H Sanders, Evan H Howlett, Jessica Sigvardson, Alex Kasrayan, Martin Ingelsson, Joakim Bergström, Anna Erlandsson
The presence of Lewy bodies, mainly consisting of aggregated α-synuclein, is a pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The α-synuclein inclusions are predominantly found in neurons, but also appear frequently in astrocytes. However, the pathological significance of α-synuclein inclusions in astrocytes and the capacity of glial cells to clear toxic α-synuclein species remain unknown. In the present study we investigated uptake, degradation and toxic effects of oligomeric α-synuclein in a co-culture system of primary neurons, astrocytes and oligodendrocytes...
April 24, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28448035/bioluminescence-imaging-of-neuroinflammation-in-transgenic-mice-after-peripheral-inoculation-of-alpha-synuclein-fibrils
#9
Sara Breid, Maria E Bernis, Julius B Tachu, Maria C Garza, Holger Wille, Gültekin Tamgüney
To study the prion-like behavior of misfolded alpha-synuclein, mouse models are needed that allow fast and simple transmission of alpha-synuclein prionoids, which cause neuropathology within the central nervous system (CNS). Here we describe that intraglossal or intraperitoneal injection of alpha-synuclein fibrils into bigenic Tg(M83(+/-):Gfap-luc(+/-)) mice, which overexpress human alpha-synuclein with the A53T mutation from the prion protein promoter and firefly luciferase from the promoter for glial fibrillary acidic protein (Gfap), is sufficient to induce neuropathologic disease...
April 13, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28442946/optogenetic-rescue-of-locomotor-dysfunction-and-dopaminergic-degeneration-caused-by-alpha-synuclein-and-eko-genes
#10
Cheng Qi, Scott Varga, Soo-Jin Oh, C Justin Lee, Daewoo Lee
α-Synuclein (α-Syn) is a small presynaptic protein and its mutant forms (e.g. A53T) are known to be directly associated with Parkinson's disease (PD). Pathophysiological mechanisms underlying α-Syn-mediated neurodegeneration in PD still remain to be explored. However, several studies strongly support that overexpression of mutant α-Syn causes reduced release of dopamine (DA) in the brain, and contributes to motor deficits in PD. Using a favorable genetic model Drosophila larva, we examined whether reduced DA release is enough to induce key PD symptoms (i...
April 2017: Experimental Neurobiology
https://www.readbyqxmd.com/read/28439961/involvement-of-the-cerebellum-in-parkinson-s-disease-and-dementia-with-lewy-bodies
#11
K Seidel, M Bouzrou, N Heidemann, R Krüger, L Schöls, Wfa den Dunnen, H-W Korf, U Rüb
Patient brains with Parkinson's disease or Dementia with Lewy bodies show aggregation of alpha-synuclein in pre-cerebellar brainstem structures. Furthermore, patients exhibit resting tremor, unstable gait and impaired balance which may be associated with cerebellar dysfunction. Therefore, we screened the cerebella of 12 patients with alpha-synucleinopathies for neuropathological changes. Cerebellar nuclei and neighboring white matter displayed numerous aggregates, while lobules were mildly affected. Cerebellar aggregation pathology may suggest a prion-like spread originating from affected precerebellar structures and the high homogeneity between patients with Dementia with Lewy bodies and Parkinson's disease shows that both diseases likely belong to the same neuropathological spectrum...
April 25, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28425704/an-ortho-iminoquinone-compound-reacts-with-lysine-inhibiting-aggregation-while-remodeling-mature-amyloid-fibrils
#12
Luiza Fernandes, Nathalia Moraes, Fernanda S Sagrillo, Augusto V Magalhães, Marcela C de Moraes, Luciana Romão, Jeffery W Kelly, Debora Foguel, Neil P Grimster, Fernando L Palhano
Protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. It has been shown that lysine residues play a key role in the formation of these aggregates. Thus, the ability to disrupt aggregate formation by covalently modifying lysine residues could lead to the discovery of therapeutically relevant antiamyloidogenesis compounds. Herein, we demonstrate that an ortho-iminoquinone (IQ) can be utilized to inhibit amyloid aggregation. Using alpha-synuclein and Aβ1-40 as model amyloidogenic proteins, we observed that IQ was able to react with lysine residues and reduce amyloid aggregation...
May 4, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28424577/investigation-of-endocytic-pathways-for-the-internalization-of-exosome-associated-oligomeric-alpha-synuclein
#13
Marion Delenclos, Teodora Trendafilova, Divya Mahesh, Ann M Baine, Simon Moussaud, Irene K Yan, Tushar Patel, Pamela J McLean
Misfolding and aggregation of alpha-synuclein (αsyn) resulting in cytotoxicity is a hallmark of Parkinson's disease (PD) and related synucleinopathies. The recent body of evidence indicates that αsyn can be released from neuronal cells by nonconventional exocytosis involving extracellular vesicles (EVs) such as exosomes. The transfer of αsyn between cells has been proposed to be an important mechanism of disease propagation in PD. To date, exosome trafficking mechanisms, including release and cell-cell transmission, have not been fully described...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28420950/metallothionein-copper-and-alpha-synuclein-in-alpha-synucleinopathies
#14
REVIEW
Yuho Okita, Alexandre N Rcom-H'cheo-Gauthier, Michael Goulding, Roger S Chung, Peter Faller, Dean L Pountney
Metallothioneins (MTs) are proteins that function by metal exchange to regulate the bioavailability of metals, such as zinc and copper. Copper functions in the brain to regulate mitochondria, neurotransmitter production, and cell signaling. Inappropriate copper binding can result in loss of protein function and Cu(I)/(II) redox cycling can generate reactive oxygen species. Copper accumulates in the brain with aging and has been shown to bind alpha-synuclein and initiate its aggregation, the primary aetiological factor in Parkinson's disease (PD), and other alpha-synucleinopathies...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28419566/perirhinal-accumulation-of-neuronal-alpha-synuclein-in-a-multiple-system-atrophy-patient-with-dementia
#15
Mari Saito, Makoto Hara, Momoko Ebashi, Akihiko Morita, Kyoko Okada, Taku Homma, Masahiko Sugitani, Kentaro Endo, Toshiki Uchihara, Satoshi Kamei
We report the case of a 79-year-old Japanese woman who developed cerebellar ataxia followed by rigidity, dysautonomia and cognitive disorders, and was thus clinically diagnosed as having possible MSA with dementia. Neuropathological findings demonstrated not only olivopontocerebellar and striatonigral degeneration with frequent glial cytoplasmic inclusions (GCIs), but also degenerative changes in the parahippocampal region, accentuated in the anterior portion of perirhinal cortex, where neuronal cytoplasmic inclusions (NCIs) and NFTs were numerous while GCIs were limited...
April 16, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/28418693/validating-the-predicted-effect-of-astemizole-and-ketoconazole-using-a-drosophila-model-of-parkinson-s-disease
#16
Katarzyna Styczyńska-Soczka, Luigi Zechini, Lysimachos Zografos
Parkinson's disease is a growing threat to an ever-ageing population. Despite progress in our understanding of the molecular and cellular mechanisms underlying the disease, all therapeutics currently available only act to improve symptoms and do not stop the disease process. It is therefore imperative that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's. Drug repurposing has been recognized as being equally as promising as de novo drug discovery in the field of neurodegeneration and Parkinson's disease specifically...
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28417442/mechanisms-of-gene-environment-interactions-in-parkinson-s-disease
#17
REVIEW
Sheila M Fleming
PURPOSE OF REVIEW: The purpose of the study was to discuss the main mechanisms associated with environmental and genetic factors that contribute to the development of Parkinson's disease (PD). RECENT FINDINGS: Novel genetic contributors to PD are being identified at a rapid pace in addition to novel environmental factors. The discovery of mutations in alpha-synuclein and leucine-rich repeat kinase 2 causing inherited forms of PD along with epidemiological, in vitro, and in vivo studies identifying herbicides, pesticides, and metals as risk factors have dramatically improved our understanding of mechanisms involved in the development of PD...
April 17, 2017: Current Environmental Health Reports
https://www.readbyqxmd.com/read/28413000/derivation-of-mouse-embryonic-stem-cell-lines-from-tyrosine-hydroxylase-reporter-mice-crossed-with-a-human-snca-transgenic-mouse-model-of-parkinson-s-disease
#18
Margarita Chumarina, Carla Azevedo, Julie Bigarreau, Clémentine Vignon, Kwang-Soo Kim, Jia-Yi Li, Laurent Roybon
Mouse embryonic stem cell (mESC) lines were derived by crossing heterozygous transgenic (tg) mice expressing green fluorescent protein (GFP) under the control of the rat tyrosine hydroxylase (TH) promoter, with homozygous alpha-synuclein (aSYN) mice expressing human mutant SNCA(A53T) under the control of the mouse Prion promoter (MoPrP), or wildtype (WT) mice. The expression of GFP and human aSYN was validated by immunocytochemistry in midbrain neuron cultures upon differentiation of mESC lines using stromal cell-derived inducing activity...
March 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28409245/snca-3-utr-genetic-variants-in-patients-with-parkinson-s-disease-and-rem-sleep-behavior-disorder
#19
M Toffoli, E Dreussi, E Cecchin, M Valente, N Sanvilli, M Montico, S Gagno, M Garziera, M Polano, M Savarese, G Calandra-Buonaura, F Placidi, M Terzaghi, G Toffoli, G L Gigli
REM sleep behavior disorder (RBD) is an early marker of Parkinson's disease (PD); however, it is still unclear which patients with RBD will eventually develop PD. Single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of alpha-synuclein (SNCA) have been associated with PD, but at present, no data is available about RBD. The 3'UTR hosts regulatory regions involved in gene expression control, such as microRNA binding sites. The aim of this study was to determine RBD specific genetic features associated to an increased risk of progression to PD, by sequencing of the SNCA-3'UTR in patients with "idiopathic" RBD (iRBD) and in patients with PD...
April 13, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28400134/alpha-synuclein-pathology-mitochondrial-dysfunction-and-neuroinflammation-in-parkinson-s-disease
#20
REVIEW
Emily M Rocha, Briana De Miranda, Laurie H Sanders
Parkinson's disease (PD) is a complex, chronic and progressive neurodegenerative disease. While the etiology of PD is likely multifactorial, the protein α-synuclein is a central component to the pathogenesis of the disease. However, the mechanism by which α-synuclein causes toxicity and contributes to neuronal death remains unclear. Mitochondrial dysfunction is also widely considered to play a major role in the underlying mechanisms contributing to neurodegeneration in PD. This review discusses evidence for the neuropathological role for α-synuclein in the dysfunction of dopamine neurons in PD...
April 8, 2017: Neurobiology of Disease
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