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https://www.readbyqxmd.com/read/28624352/pressure-effects-on-%C3%AE-synuclein-amyloid-fibrils-an-experimental-investigation-on-their-dissociation-and-reversible-nature
#1
Federica Piccirilli, Nicoletta Plotegher, Francesco Spinozzi, Luigi Bubacco, Paolo Mariani, Mariano Beltramini, Isabella Tessari, Valeria Militello, Andrea Perucchi, Heinz Wilfried Amenitsch, Enrico Baldassarri, Milos Steinhart, Stefano Lupi, Maria Grazia Ortore
α-synuclein amyloid fibrils are found in surviving neurons of Parkinson's disease affected patients, but the role they play in the disease development is still under debate. A growing number of evidences points to soluble oligomers as the major cytotoxic species, while insoluble fibrillar aggregates could even play a protection role. In this work, we investigate α-synuclein fibrils dissociation induced at high pressure by means of Small Angle X-ray Scattering and Fourier Transform Infrared Spectroscopy. Fibrils were produced from wild type α-synuclein and two familial mutants, A30P and A53T...
June 14, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28623611/deferiprone-rescues-behavioral-deficits-induced-by-mild-iron-exposure-in-a-mouse-model-of-alpha-synuclein-aggregation
#2
Eleonora Carboni, Lars Tatenhorst, Lars Tönges, Elisabeth Barski, Vivian Dambeck, Mathias Bähr, Paul Lingor
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and its causes remain unknown. A major hallmark of the disease is the increasing presence of aggregated alpha-synuclein (aSyn). Furthermore, there is a solid consensus on iron (Fe) accumulation in several regions of PD brains during disease progression. In our study, we focused on the interaction of Fe and aggregating aSyn in vivo in a transgenic mouse model overexpressing human aSyn bearing the A53T mutation (prnp.aSyn.A53T). We utilized a neonatal iron-feeding model to exacerbate the motor phenotype of the transgenic mouse model...
June 16, 2017: Neuromolecular Medicine
https://www.readbyqxmd.com/read/28619113/mechanisms-underlying-extensive-ser129-phosphorylation-in-%C3%AE-synuclein-aggregates
#3
Shigeki Arawaka, Hiroyasu Sato, Asuka Sasaki, Shingo Koyama, Takeo Kato
Parkinson's disease (PD) is characterized neuropathologically by intracellular aggregates of fibrillar α-synuclein, termed Lewy bodies (LBs). Approximately 90% of α-synuclein deposited as LBs is phosphorylated at Ser129 in brains with PD. In contrast, only 4% of total α-synuclein is phosphorylated at Ser129 in brains with normal individuals. It is unclear why extensive phosphorylation occurs in the pathological process of PD. To address this issue, we investigated a mechanism and role of Ser129-phosphorylation in regulating accumulation of α-synuclein...
June 15, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28580639/mesenchymal-stem-cells-stabilize-axonal-transports-for-autophagic-clearance-of-%C3%AE-synuclein-in-parkinsonian-models
#4
Se Hee Oh, Seok Cheol Lee, Dong Yeol Kim, Ha Na Kim, Jin Young Shin, Byoung Seok Ye, Phil Hyu Lee
Genome-wide association studies have identified two loci, SNCA and the microtubule (MT)-associated protein tau, as common risk factors for Parkinson's disease (PD). Specifically, α-synuclein directly destabilizes MT via tau phosphorylation and induces axonal transport deficits that are the primary events leading to an abnormal accumulation of α-synuclein that causes nigral dopaminergic cell loss. In the present study, we demonstrated that mesenchymal stem cells (MSCs) could modulate cytoskeletal networks and trafficking to exert neuroprotective properties in wild-type or A53T α-synuclein overexpressing cells and mice...
June 5, 2017: Stem Cells
https://www.readbyqxmd.com/read/28576942/wild-type-monomeric-%C3%AE-synuclein-can-impair-vesicle-endocytosis-and-synaptic-fidelity-via-tubulin-polymerization-at-the-calyx-of-held
#5
Kohgaku Eguchi, Zacharie Taoufiq, Oliver Thorn-Seshold, Dirk Trauner, Masato Hasegawa, Tomoyuki Takahashi
α-Synuclein is a presynaptic protein, the function of which has as yet to be identified, but its neuronal content increases in patients of synucleinopathies including Parkinson's disease. Chronic overexpression of α-synuclein reportedly expresses various phenotypes of synaptic dysfunction, but the primary target of its toxicity has not been determined. To investigate this, we acutely loaded human recombinant α-synuclein or its pathological mutants in their monomeric forms into the calyces of Held presynaptic terminals in slices from auditorily mature and immature rats of either sexes...
June 2, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28573674/overexpression-of-%C3%AE-synuclein-in-an-astrocyte-cell-line-promotes-autophagy-inhibition-and-apoptosis
#6
Adolfo Garcia Erustes, Fernanda Yakel Stefani, Juliana Yoshie Terashima, Roberta Sessa Stilhano, Priscila Totarelli Monteforte, Gustavo José da Silva Pereira, Sang Won Han, Andrana Karla Calgarotto, Yi-Te Hsu, Rodrigo Portes Ureshino, Cláudia Bincoletto, Soraya Soubhi Smaili
α-Synuclein is the major component of neuronal cytoplasmic aggregates called Lewy bodies, the main pathological hallmark of Parkinson disease. Although neurons are the predominant cells expressing α-synuclein in the brain, recent studies have demonstrated that primary astrocytes in culture also express α-synuclein and regulate α-synuclein trafficking. Astrocytes have a neuroprotective role in several detrimental brain conditions; we therefore analyzed the effects of the overexpression of wild-type α-synuclein and its A30P and A53T mutants on autophagy and apoptosis...
June 2, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28569795/cystatin-c-as-a-potential-therapeutic-mediator-against-parkinson-s-disease-via-vegf-induced-angiogenesis-and-enhanced-neuronal-autophagy-in-neurovascular-units
#7
Jing Zou, Zhaoyu Chen, Xiaobo Wei, Zhigang Chen, Yongmei Fu, Xiaoyan Yang, Dan Chen, Rui Wang, Peter Jenner, Jia-Hong Lu, Min Li, Zhuohua Zhang, Beisha Tang, Kunlin Jin, Qing Wang
Cystatin C (CYS C, Cst3) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson's disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T α-synuclein (SNCA) transgenic mice and 6-hydroxydopamine-lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice...
June 1, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28562630/the-influence-of-n-terminal-acetylation-on-micelle-induced-conformational-changes-and-aggregation-of-%C3%AE-synuclein
#8
David Ruzafa, Yuriko S Hernandez-Gomez, Giovanni Bisello, Kerensa Broersen, Bertrand Morel, Francisco Conejero-Lara
The biological function of α-Synuclein has been related to binding to lipids and membranes but these interactions can also mediate α-Synuclein aggregation, which is associated to Parkinson's disease and other neuropathologies. In brain tissue α-Synuclein is constitutively N-acetylated, a modification that plays an important role in its conformational propensity, lipid and membrane binding, and aggregation propensity. We studied the interactions of the lipid-mimetic SDS with N-acetylated and non-acetylated α-Synuclein, as well as their early-onset Parkinson's disease variants A30P, E46K and A53T...
2017: PloS One
https://www.readbyqxmd.com/read/28520872/glucocerebrosidase-deficiency-in-dopaminergic-neurons-induces-microglial-activation-without-neurodegeneration
#9
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/28482862/higher-levels-of-myelin-phospholipids-in-brains-of-neuronal-%C3%AE-synuclein-transgenic-mice-precede-myelin-loss
#10
Jessica Grigoletto, Katharina Pukaß, Ayelet Gamliel, Dana Davidi, Rachel Katz-Brull, Christiane Richter-Landsberg, Ronit Sharon
α-Synuclein is a protein involved in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We investigated the role of neuronal α-Syn in myelin composition and abnormalities. The phospholipid content of purified myelin was determined by (31)P NMR in two mouse lines modeling PD, PrP-A53T α-Syn and Thy-1 wt-α-Syn. Significantly higher levels of phospholipids were detected in myelin purified from brains of these α-Syn transgenic mouse models than in control mice...
May 8, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28476570/expression-signatures-of-long-non-coding-rna-in-the-substantia-nigra-of-pre-symptomatic-mouse-model-of-parkinson-s-disease
#11
Fengjuan Jiao, Qingzhi Wang, Pei Zhang, Lulu Bu, Jianguo Yan, Bo Tian
Parkinson's disease (PD) is an age-dependent neurodegenerative disease that can be caused by a variety of factors. Growing evidence shows that prior to the motor phase of PD can express molecular or imaging markers. Many long non-coding RNAs (lncRNAs) have been identified in neurodegenerative disease. However, the biogenesis and function of lncRNAs in the pre-symptomatic stage of PD is poorly understood. Here, we profiled the expression of lncRNAs and mRNAs in the substantia nigra pars compacta (SNpc) of pre-symptomatic mice over-expressing human A30P*A53T α-synuclein by microarray analysis...
May 2, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28470693/subthalamic-nucleus-deep-brain-stimulation-is-neuroprotective-in-the-a53t-%C3%AE-synuclein-parkinson-s-disease-rat-model
#12
Thomas Musacchio, Maike Rebenstorff, Felix Fluri, Jonathan M Brotchie, Jens Volkmann, James B Koprich, Chi Wang Ip
OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective symptomatic therapy for motor deficits in Parkinson's disease (PD). An additional, disease-modifying effect has been suspected from studies in toxin-based PD animal models, but these models do not reflect the molecular pathology and progressive nature of PD that would be required to evaluate a disease-modifying action. Defining a disease-modifying effect could radically change the way in which DBS is used in PD...
May 3, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28448035/bioluminescence-imaging-of-neuroinflammation-in-transgenic-mice-after-peripheral-inoculation-of-alpha-synuclein-fibrils
#13
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
#14
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/28416701/defective-synaptic-connectivity-and-axonal-neuropathology-in-a-human-ipsc-based-model-of-familial-parkinson-s-disease
#15
Georgia Kouroupi, Era Taoufik, Ioannis S Vlachos, Konstantinos Tsioras, Nasia Antoniou, Florentia Papastefanaki, Dafni Chroni-Tzartou, Wolfgang Wrasidlo, Delphine Bohl, Dimitris Stellas, Panagiotis K Politis, Kostas Vekrellis, Dimitra Papadimitriou, Leonidas Stefanis, Piotr Bregestovski, Artemis G Hatzigeorgiou, Eliezer Masliah, Rebecca Matsas
α-Synuclein (αSyn) is the major gene linked to sporadic Parkinson's disease (PD), whereas the G209A (p.A53T) αSyn mutation causes a familial form of PD characterized by early onset and a generally severe phenotype, including nonmotor manifestations. Here we generated de novo induced pluripotent stem cells (iPSCs) from patients harboring the p.A53T mutation and developed a robust model that captures PD pathogenic processes under basal conditions. iPSC-derived mutant neurons displayed novel disease-relevant phenotypes, including protein aggregation, compromised neuritic outgrowth, and contorted or fragmented axons with swollen varicosities containing αSyn and Tau...
May 2, 2017: Proceedings of the National Academy of Sciences of the United States of America
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
#16
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/28373279/a-sensitive-assay-reveals-structural-requirements-for-%C3%AE-synuclein-fibril-growth
#17
Dhruva D Dhavale, Christina Tsai, Devika P Bagchi, Laura A Engel, Jonathan Sarezky, Paul T Kotzbauer
The accumulation of α-synuclein (α-syn) fibrils in neuronal inclusions is the defining pathological process in Parkinson's disease (PD). A pathogenic role for α-syn fibril accumulation is supported by the identification of dominantly inherited α-syn (SNCA) gene mutations in rare cases of familial PD. Fibril formation involves a spontaneous nucleation event in which soluble α-syn monomers associate to form seeds, followed by fibril growth during which monomeric α-syn molecules sequentially associate with existing seeds...
June 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28360124/genetic-mutations-linked-to-parkinson-s-disease-differentially-control-nucleolar-activity-in-pre-symptomatic-mouse-models
#18
Valentin Evsyukov, Andrii Domanskyi, Holger Bierhoff, Suzana Gispert, Rasem Mustafa, Falk Schlaudraff, Birgit Liss, Rosanna Parlato
Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting that nucleolar dysfunction could be a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human α-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1...
May 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28300069/extracellular-%C3%AE-synuclein-induces-sphingosine-1-phosphate-receptor-subtype-1-uncoupled-from-inhibitory-g-protein-leaving-%C3%AE-arrestin-signal-intact
#19
Lifang Zhang, Taro Okada, Shaymaa Mohamed Mohamed Badawy, Chihoko Hirai, Taketoshi Kajimoto, Shun-Ichi Nakamura
Parkinson's disease (PD) is the second most common neurodegenerative disorder. The presence of α-synuclein (α-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies, is the cytopathological hallmark of PD. Increasing bodies of evidence suggest that cell-to-cell transmission of α-Syn plays a role in the progression of PD. Although extracellular α-Syn is known to cause abnormal cell motility, the precise mechanism remains elusive. Here we show that impairment of platelet-derived growth factor-induced cell motility caused by extracellular α-Syn is mainly attributed to selective inhibition of sphingosine 1-phosphate (S1P) signalling...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28223512/glucosylceramide-synthase-inhibition-alleviates-aberrations-in-synucleinopathy-models
#20
S Pablo Sardi, Catherine Viel, Jennifer Clarke, Christopher M Treleaven, Amy M Richards, Hyejung Park, Maureen A Olszewski, James C Dodge, John Marshall, Elina Makino, Bing Wang, Richard L Sidman, Seng H Cheng, Lamya S Shihabuddin
Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, Gba(D409V/D409V) and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
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