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Alpha-synuclein

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https://www.readbyqxmd.com/read/28631520/striatal-changes-underlie-mpep-mediated-suppression-of-the-acquisition-and-expression-of-pramipexole-induced-place-preference-in-an-alpha-synuclein-rat-model-of-parkinson-s-disease
#1
Simon Loiodice, Portia McGhan, Vitalina Gryshkova, Renaud Fleurance, David Dardou, Aziz Hafidi, Andre Nogueira da Costa, Franck Durif
Impulsive-compulsive disorders in Parkinson's disease patients have been described as behavioural or substance addictions including pathological gambling or compulsive medication use of dopamine replacement therapy. A substantial gap remains in the understanding of these disorders. We previously demonstrated that the rewarding effect of the D2/D3 agonist pramipexole was enhanced after repeated exposure to L-dopa and alpha-synuclein mediated dopaminergic nigral loss with specific transcriptional signatures suggesting a key involvement of the glutamatergic pathway...
June 1, 2017: Journal of Psychopharmacology
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/28621812/tcdd-induces-ubch7-expression-and-synphilin-1-protein-degradation-in-the-mouse-ventral-midbrain
#3
Emmanuel González-Barbosa, Alejandro Mejía-García, Elizabeth Bautista, Frank J Gonzalez, José Segovia, Guillermo Elizondo
UbcH7 is an ubiquitin-conjugating enzyme that interacts with parkin, an E3 ligase. The UbcH7-parkin complex promotes the ubiquitination and degradation of several proteins via the 26S proteasome. Cellular accumulation of the UbcH7-parkin targets alpha-synuclein, and synphilin-1 has been associated with Parkinson disease. In mouse liver, 2,3,7,8-tetrachlorodibenzo-p-dioxin, an aryl hydrocarbon receptor ligand, induces UbcH7 expression. Therefore, the aim of the present study was to determine whether 2,3,7,8-tetrachlorodibenzo-p-dioxin induces Ubch7 mRNA and UbcH7 protein expression in the mouse brain, to characterize the molecular mechanism, and the effect on synphilin-1 half-life...
June 16, 2017: Journal of Biochemical and Molecular Toxicology
https://www.readbyqxmd.com/read/28620826/individual-amino-acid-supplementation-can-improve-energy-metabolism-and-decrease-ros-production-in-neuronal-cells-overexpressing-alpha-synuclein
#4
Vedad Delic, Jeddidiah W D Griffin, Sandra Zivkovic, Yumeng Zhang, Tam-Anh Phan, Henry Gong, Dale Chaput, Christian Reynes, Vinh B Dinh, Josean Cruz, Eni Cvitkovic, Devon Placides, Ernide Frederic, Hamed Mirzaei, Stanley M Stevens, Umesh Jinwal, Daniel C Lee, Patrick C Bradshaw
Parkinson's disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein accumulation and loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. Increased levels of alpha-synuclein have been shown to result in loss of mitochondrial electron transport chain complex I activity leading to increased reactive oxygen species (ROS) production. WT alpha-synuclein was stably overexpressed in human BE(2)-M17 neuroblastoma cells resulting in increased levels of an alpha-synuclein multimer, but no increase in alpha-synuclein monomer levels...
June 15, 2017: Neuromolecular Medicine
https://www.readbyqxmd.com/read/28619074/novel-oligodendroglial-alpha-synuclein-viral-vector-models-of-multiple-system-atrophy-studies-in-rodents-and-nonhuman-primates
#5
Ronald J Mandel, David J Marmion, Deniz Kirik, Yaping Chu, Clifford Heindel, Thomas McCown, Steven J Gray, Jeffrey H Kordower
Multiple system atrophy (MSA) is a horrible and unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein (α-syn) accumulates preferentially in oligodendroglia rather than neurons. Glial cytoplasmic inclusions (GCIs) of α-syn are thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. To date, only a murine model using one of three promoters exist to study this disease...
June 16, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28611062/selective-imaging-of-internalized-proteopathic-%C3%AE-synuclein-seeds-in-primary-neurons-reveals-mechanistic-insight-into-transmission-of-synucleinopathies
#6
Richard J Karpowicz, Conor M Haney, Tiberiu S Mihaila, Raizel M Sandler, E James Petersson, Virginia M-Y Lee
Direct cell-to-cell transmission of proteopathic alpha-synuclein (α-syn) aggregates is thought to underlie the progression of neurodegenerative synucleinopathies. However, the specific intracellular processes governing this transmission remain unclear because currently-available model systems are limited. For example, in cell culture models of α-syn-seeded aggregation, it is difficult to discern intracellular from extracellular exogenously applied α-syn seed species. Herein, we employed fluorescently labeled α-syn preformed fibrils (pffs) in conjunction with the membrane-impermeable fluorescence quencher trypan blue to selectively image internalized α-syn seeds in cultured primary neurons and to quantitatively characterize the concentration dependence, time course, and inhibition of pff uptake...
June 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28604235/discovery-validation-and-optimization-of-cerebrospinal-fluid-biomarkers-for-use-in-parkinson-s-disease
#7
Lucia Farotti, Silvia Paciotti, Anna Tasegian, Paolo Eusebi, Lucilla Parnetti
Parkinson's disease (PD) is a complex and phenotypically heterogeneous neurodegenerative disease, for which the diagnosis is mainly based on clinical parameters (even if neuroimaging plays a role in diagnostic assessment); as a consequence, misdiagnosis is common, especially in early stages. Thus, there is an urgent need of having available biomarkers in order to achieve an early and accurate diagnosis. Since molecular changes in the brain are reliably and timely reflected in cerebrospinal fluid (CSF), CSF represents an ideal source for biomarkers of different pathophysiological processes characterizing the disease since its early phases...
June 19, 2017: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/28603514/cutaneous-autonomic-pilomotor-testing-to-unveil-the-role-of-neuropathy-progression-in-early-parkinson-s-disease-capture-pd-protocol-for-a-multicenter-study
#8
Timo Siepmann, Alexandra Pintér, Sylvia J Buchmann, Leonie Stibal, Martin Arndt, Anne Sophie Kubasch, Marie Luise Kubasch, Ana Isabel Penzlin, Elka Frenz, Wagner Zago, Tamás Horváth, Szabolcs Szatmári, Dániel Bereczki, Annamária Takáts, Tjalf Ziemssen, Axel Lipp, Roy Freeman, Heinz Reichmann, Kristian Barlinn, Ben Min-Woo Illigens
BACKGROUND: In Parkinson's disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function via quantitative direct and indirect test of sudomotor function...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28598856/glucocerebrosidase-mutations-in-parkinson-disease
#9
Grace O'Regan, Ruth-Mary deSouza, Roberta Balestrino, A H Schapira
Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD...
June 7, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28595912/the-effect-of-manganese-exposure-in-atp13a2-deficient-mice
#10
Sheila M Fleming, Nicholas A Santiago, Elizabeth J Mullin, Shanta Pamphile, Swagata Karkare, Andrew Lemkuhl, Osunde R Ekhator, Stephen C Linn, John G Holden, Diana S Aga, Jerome A Roth, Benjamin Liou, Ying Sun, Gary E Shull, Patrick J Schultheis
Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice...
June 6, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28582870/cutaneous-alpha-synuclein-from-paraffin-embedded-autopsy-specimens-in-parkinson-s-disease
#11
Christopher H Gibbons, Ningshan Wang, Roy Freeman
BACKGROUND: Parkinson disease (PD) is neurodegenerative disorder characterized by tremor, rigidity and bradykinesia and pathologically by the deposition of alpha-synuclein within different tissues. We, and others, have reported the detection of cutaneous alpha-synuclein in individuals with PD. OBJECTIVE: The goal of the present study was to detect alpha-synuclein deposition by immunohistochemical staining of skin samples in pathologically confirmed cases of PD. METHODS: Post-mortem skin biopsy samples from 11 individuals with PD, and 5 non-synucleinopathy control subjects were paraffin embedded and stained for total alpha-synuclein and protein gene product 9...
May 31, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28571531/c-abl-inhibition-a-novel-therapeutic-target-for-parkinson-s-disease
#12
Abdelrahman Ibrahim Abushouk, Ahmed Negida, Rasha Abdelsalam Elshenawy, Hossam Zein, Ali M Hammad, Ahmed Menshawy, Wael M Y Mohamed
Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. To the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of PD. However, due to ignorance of the main pathological sequence of PD, many drug targets failed recently to provide neuroprotective effects in human trials...
June 1, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28568905/tmem230-how-does-it-fit-in-the-etiology-and-pathogenesis-of-parkinson-s-disease
#13
REVIEW
Wim Mandemakers, Marialuisa Quadri, Maria Stamelou, Vincenzo Bonifati
Mutations in the transmembrane protein 230 (TMEM230) gene were recently identified in a large Canadian pedigree and 7 smaller Chinese families, nominating TMEM230 as the third gene causing a Mendelian form of late onset Parkinson's disease (PD) with typical Lewy-body pathology (after synuclein alpha (SNCA) and leucine rich repeat kinase 2 (LRRK2)). The protein encoded by TMEM230 remains largely uncharacterized, but initial evidence points to roles in the trafficking of recycling vesicles, retromers, and endosomes, suggesting intriguing links to the pathways targeted by other PD-causing genes...
June 1, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28568506/pbb3-imaging-in-parkinsonian-disorders-evidence-for-binding-to-tau-and-other-proteins
#14
Alexandra Perez-Soriano, Julieta E Arena, Katie Dinelle, Qing Miao, Jessamyn McKenzie, Nicole Neilson, Andreas Puschmann, Paul Schaffer, Hitoshi Shinotoh, Jenna Smith-Forrester, Elham Shahinfard, Nasim Vafai, Daryl Wile, Zbigniew Wszolek, Makoto Higuchi, Vesna Sossi, A Jon Stoessl
BACKGROUND AND OBJECTIVES: To study selective regional binding for tau pathology in vivo, using PET with [(11) C]PBB3 in PSP patients, and other conditions not typically associated with tauopathy. METHODS: Dynamic PET scans were obtained for 70 minutes after the bolus injection of [(11) C]PBB3 in 5 PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype, 3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 6 healthy controls of similar age. Tissue reference Logan analysis was applied to each region of interest using a cerebellar white matter reference region...
June 1, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28556404/viral-mediated-oligodendroglial-alpha-synuclein-expression-models-multiple-system-atrophy
#15
Fares Bassil, Paul A Guerin, Nathalie Dutheil, Qin Li, Matthias Klugmann, Wassilios G Meissner, Erwan Bezard, Pierre-Olivier Fernagut
BACKGROUND: MSA is a fatal neurodegenerative disorder characterized by a combination of autonomic dysfunction, cerebellar ataxia, and l-dopa unresponsive parkinsonism. The hallmark of MSA is the accumulation of α-synuclein, forming cytoplasmic inclusions in oligodendrocytes. Adeno-associated viruses allow efficient targeting of disease-associated genes in selected cellular ensembles and have proven efficient for the neuronal overexpression of α-synuclein in the substantia nigra in the context of PD...
May 29, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28549787/the-gut-brain-axis-in-parkinson-s-disease-possibilities-for-food-based-therapies
#16
Paula Perez-Pardo, Tessa Kliest, Hemraj B Dodiya, Laus M Broersen, Johan Garssen, Ali Keshavarzian, Aletta D Kraneveld
Parkinson's disease (PD) is usually characterized by cardinal motor impairments. However, a range of non-motor symptoms precede the motor-phase and are major determinants for the quality of life. To date, no disease modifying treatment is available for PD patients. The gold standard therapy of levodopa is based on restoring dopaminergic neurotransmission, thereby alleviating motor symptoms, whereas non-motor symptoms remain undertreated. One of the most common non-motor symptoms is gastrointestinal dysfunction usually associated with alpha-synuclein accumulations and low-grade mucosal inflammation in the enteric nervous system...
May 23, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28540131/parkinson-s-disease-microglial-macrophage-induced-immunoexcitotoxicity-as-a-central-mechanism-of-neurodegeneration
#17
REVIEW
Russell L Blaylock
Parkinson's disease is one of the several neurodegenerative disorders that affects aging individuals, with approximately 1% of those over the age of 60 years developing the disorder in their lifetime. The disease has the characteristics of a progressive disorder in most people, with a common pattern of pathological change occurring in the nervous system that extends beyond the classical striatal degeneration of dopaminergic neurons. Earlier studies concluded that the disease was a disorder of alpha-synuclein, with the formation of aggregates of abnormal alpha-synuclein being characteristic...
2017: Surgical Neurology International
https://www.readbyqxmd.com/read/28534083/synthetic-alpha-synuclein-fibrils-cause-mitochondrial-impairment-and-selective-dopamine-neurodegeneration-in-part-via-inos-mediated-nitric-oxide-production
#18
Victor Tapias, Xiaoping Hu, Kelvin C Luk, Laurie H Sanders, Virginia M Lee, J Timothy Greenamyre
Intracellular accumulation of α-synuclein (α-syn) are hallmarks of synucleinopathies, including Parkinson's disease (PD). Exogenous addition of preformed α-syn fibrils (PFFs) into primary hippocampal neurons induced α-syn aggregation and accumulation. Likewise, intrastriatal inoculation of PFFs into mice and non-human primates generates Lewy bodies and Lewy neurites associated with PD-like neurodegeneration. Herein, we investigate the putative effects of synthetic human PFFs on cultured rat ventral midbrain dopamine (DA) neurons...
May 22, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28526239/cellular-models-as-tools-for-the-study-of-the-role-of-alpha-synuclein-in-parkinson-s-disease
#19
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
#20
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
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