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Alpha synuclein

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https://www.readbyqxmd.com/read/28921554/dj-1-deficiency-impairs-autophagy-and-reduces-alpha-synuclein-phagocytosis-by-microglia
#1
Yuval Nash, Eran Schmukler, Dorit Trudler, Ronit Pinkas-Kramarski, Dan Frenkel
Parkinson's disease (PD) is a progressive neurodegenerative disorder, of which 1% of the hereditary cases are linked to mutations in DJ-1, an oxidative stress sensor. The pathological hallmark of PD is intercellular inclusions termed Lewy Bodies, composed mainly of α-Synuclein (α-Syn) protein. Recent findings have shown that α-Syn can be transmitted from cell to cell, suggesting an important role of microglia, as the main scavenger cells of the brain, in clearing α-Syn. We previously reported that the knock down (KD) of DJ-1 in microglia increased cells' neurotoxicity to dopaminergic neurons...
September 16, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28912345/a-novel-bibenzyl-compound-20c-protected-mice-from-mptp-p-toxicity-by-regulating-alpha-synuclein-related-inflammatory-response
#2
Qiu-Shuang Zhang, Yang Heng, Ying Chen, Piao Luo, Lu Wen, Zhao Zhang, Yu-He Yuan, Nai-Hong Chen
The novel bibenzyl compound 20C plays a neuroprotective role in vitro, but its effects in vivo have not been elucidated. In this study, we estimated the efficacy of 20C in vivo using a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p) mouse model from behavior, dopamine and neuron, and then the possible mechanisms for these effects were further investigated. The experimental results showed that 20C improved behavioral deficits, attenuated dopamine depletion, reduced dopaminergic neuron loss, protected blood brain barrier structure, ameliorated α-synuclein dysfunction, suppressed glial activation, and regulated both NF-κB signaling and the NLRP3 inflammasome pathway...
September 14, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28904388/protective-efficacy-of-phosphodiesterase-1-inhibition-against-alpha-synuclein-toxicity-revealed-by-compound-screening-in-luhmes-cells
#3
Matthias Höllerhage, Claudia Moebius, Johannes Melms, Wei-Hua Chiu, Joachim N Goebel, Tasnim Chakroun, Thomas Koeglsperger, Wolfgang H Oertel, Thomas W Rösler, Marc Bickle, Günter U Höglinger
α-synuclein-induced neurotoxicity is a core pathogenic event in neurodegenerative synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs for their efficacy to protect LUHMES cells from degeneration induced by wild-type α-synuclein and identified dipyridamole, a non-selective phosphodiesterase inhibitor, as top hit. Systematic analysis of other phosphodiesterase inhibitors identified a specific phosphodiesterase 1 inhibitor as most potent to rescue from α-synuclein toxicity...
September 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28900170/protein-arginylation-targets-alpha-synuclein-facilitates-normal-brain-health-and-prevents-neurodegeneration
#4
Junling Wang, Xuemei Han, Nicolae Adrian Leu, Stephanie Sterling, Satoshi Kurosaka, Marie Fina, Virginia M Lee, Dawei W Dong, John R Yates, Anna Kashina
Alpha synuclein (α-syn) is a central player in neurodegeneration, but the mechanisms triggering its pathology are not fully understood. Here we found that α-syn is a highly efficient substrate for arginyltransferase ATE1 and is arginylated in vivo by a novel mid-chain mechanism that targets the acidic side chains of E46 and E83. Lack of arginylation leads to increased α-syn aggregation and causes the formation of larger pathological aggregates in neurons, accompanied by impairments in its ability to be cleared via normal degradation pathways...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28895489/effects-of-mild-running-on-substantia-nigra-during-early-neurodegeneration
#5
Michael F Almeida, Carolliny M Silva, Rodrigo S Chaves, Nathan C R Lima, Renato S Almeida, Karla P Melo, Marilene Demasi, Tiago Fernandes, Edilamar M Oliveira, Luis E S Netto, Sandra M Cardoso, Merari F R Ferrari
Moderate physical exercise acts at molecular and behavioural levels, such as interfering in neuroplasticity, cell death, neurogenesis, cognition and motor functions. Therefore, the aim of this study is to analyse the cellular effects of moderate treadmill running upon substantia nigra during early neurodegeneration. Aged male Lewis rats (9-month-old) were exposed to rotenone 1mg/kg/day (8 weeks) and 6 weeks of moderate treadmill running, beginning 4 weeks after rotenone exposure. Substantia nigra was extracted and submitted to proteasome and antioxidant enzymes activities, hydrogen peroxide levels and Western blot to evaluate tyrosine hydroxylase (TH), alpha-synuclein, Tom-20, PINK1, TrkB, SLP1, CRMP-2, Rab-27b, LC3II and Beclin-1 level...
September 12, 2017: Journal of Sports Sciences
https://www.readbyqxmd.com/read/28892570/dnajc12-and-dopa-responsive-non-progressive-parkinsonism
#6
Letizia Straniero, Ilaria Guella, Roberto Cilia, Laura Parkkinen, Valeria Rimoldi, Alexander Young, Rosanna Asselta, Giulia Soldà, Vesna Sossi, A Jon Stoessl, Alberto Priori, Kenya Nishioka, Nobutaka Hattori, Jordan Follett, Alex Rajput, Nenad Blau, Gianni Pezzoli, Matthew J Farrer, Stefano Goldwurm, Ali H Rajput, Stefano Duga
Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia. We identified DNAJC12 homozygous null variants (c.187A>T;p.K63*and c.79-2A>G;p.V27Wfs*14) in two kindreds with early-onset parkinsonism. Both probands had mild intellectual disability, mild non-progressive, motor symptoms, sustained benefit from small dose of levodopa and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband-A) revealed no alpha-synuclein pathology and substantia nigra depigmentation with moderate cell loss DNAJC12 transcripts were reduced in both patients...
September 11, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28889266/occupational-metal-exposure-and-parkinsonism
#7
W Michael Caudle
Parkinsonism is comprised of a host of neurological disorders with an underlying clinical feature of movement disorder, which includes many shared features of bradykinesia, tremor, and rigidity. These clinical outcomes occur subsequent to pathological deficits focused on degeneration or dysfunction of the nigrostriatal dopamine system and accompanying pathological inclusions of alpha-synuclein and tau. The heterogeneity of parkinsonism is equally matched with the complex etiology of this syndrome. While a small percentage can be attributed to genetic alterations, the majority arise from an environmental exposure, generally composed of pesticides, industrial compounds, as well as metals...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28877262/the-er-retention-protein-rer1-promotes-alpha-synuclein-degradation-via-the-proteasome
#8
Hyo-Jin Park, Daniel Ryu, Mayur Parmar, Benoit I Giasson, Nikolaus R McFarland
Abnormal accumulation of α-synuclein (αSyn) has been linked to endoplasmic-reticulum (ER) stress, defective intracellular protein/vesicle trafficking, and cytotoxicity. Targeting factors involved in ER-related protein processing and trafficking may, therefore, be a key to modulating αSyn levels and associated toxicity. Recently retention in endoplasmic reticulum 1 (RER1) has been identified as an important ER retrieval/retention factor for Alzheimer's disease proteins and negatively regulates amyloid-β peptide levels...
2017: PloS One
https://www.readbyqxmd.com/read/28875469/a-panel-of-autoantibodies-against-neural-proteins-as-peripheral-biomarker-for-pesticide-induced-neurotoxicity
#9
Heba Allah Abd El Rahman, Mohamed Salama, Seham A Gad El-Hak, Mona A El-Harouny, Passent ElKafrawy, Mohamed B Abou-Donia
In the present study, we screened the sera of subjects chronically exposed to mixtures of pesticides (composed mainly of organophosphorus compounds (OPs) and others) and developed neurological symptoms for the presence of autoantibodies against cytoskeletal neural proteins. OPs have a well-characterized clinical profile resulting from acute cholinergic crisis. However, some of these compounds cause neuronal degeneration and demyelination known as organophosphorus compound-induced delayed neurotoxicity (OPIDN) and/or organophosphorus compound-induced chronic neurotoxicity (OPICN)...
September 5, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28874699/metal-concentrations-and-distributions-in-the-human-olfactory-bulb-in-parkinson-s-disease
#10
Bronwen Gardner, Birger V Dieriks, Steve Cameron, Lakshini H S Mendis, Clinton Turner, Richard L M Faull, Maurice A Curtis
In Parkinson's disease (PD), the olfactory bulb is typically the first region in the body to accumulate alpha-synuclein aggregates. This pathology is linked to decreased olfactory ability, which becomes apparent before any motor symptoms occur, and may be due to a local metal imbalance. Metal concentrations were investigated in post-mortem olfactory bulbs and tracts from 17 human subjects. Iron (p < 0.05) and sodium (p < 0.01) concentrations were elevated in the PD olfactory bulb. Combining laser ablation inductively coupled plasma mass spectrometry and immunohistochemistry, iron and copper were evident at very low levels in regions of alpha-synuclein aggregation...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28870518/multitep-platform-based-dna-vaccines-for-alpha-synucleinopathies-preclinical-evaluation-of-immunogenicity-and-therapeutic-potency
#11
Hayk Davtyan, Karen Zagorski, Irina Petrushina, Konstantin Kazarian, Natalie R S Goldberg, Janet Petrosyan, Mathew Blurton-Jones, Eliezer Masliah, David H Cribbs, Michael G Agadjanyan, Anahit Ghochikyan
We have previously demonstrated that anti-beta amyloid DNA vaccine (AV-1959D) based on our proprietary MultiTEP platform technology is extremely immunogenic in mice, rabbits, and monkeys. Importantly, MultiTEP platform enables development of vaccines targeting pathological molecules involved in various neurodegenerative disorders. Taking advantage of the universality of MultiTEP platform, we developed DNA vaccines targeting 3 B-cell epitopes (amino acids [aa]85-99, aa109-126, and aa126-140) of human alpha-synuclein (hα-Syn) separately or all 3 epitopes simultaneously...
August 10, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28866688/alpha-synuclein-to-the-rescue-immune-cell-recruitment-by-alpha-synuclein-during-gastrointestinal-infection
#12
Viviane Labrie, Patrik Brundin
Intraneuronal accumulation of misfolded alpha-synuclein in the central and peripheral nervous systems is strongly linked to Parkinson disease (PD) and other related synucleinopathies. In rare inherited forms of PD, point mutations or gene multiplications mediate the formation of alpha-synuclein protein aggregates. However, in most PD cases it is presumed that the combined effects of ageing and environmental factors drive the formation of alpha-synuclein aggregates. Despite advances regarding alpha-synuclein pathobiology, the normal functions of this protein and factors that regulate its expression are not well understood...
September 2, 2017: Journal of Innate Immunity
https://www.readbyqxmd.com/read/28863169/effects-of-small-molecule-amyloid-modulators-on-a-drosophila-model-of-parkinson-s-disease
#13
Małgorzata Pokrzywa, Katarzyna Pawełek, Weronika Elżbieta Kucia, Szymon Sarbak, Erik Chorell, Fredrik Almqvist, Pernilla Wittung-Stafshede
Alpha-synuclein (aS) amyloid formation is involved in Parkinson's disease (PD); therefore, small molecules that target aS and affect its aggregation are of interest as future drug candidates. We recently reported modified ring-fused 2-pyridones that modulate aS amyloid formation in vitro. Here, we describe the effects of such molecules on behavioral parameters of a Drosophila model of PD (i.e., flies expressing human aS), using a new approach (implemented in a commercially available FlyTracker system) to quantify fly mobility...
2017: PloS One
https://www.readbyqxmd.com/read/28852398/how-does-conserved-dopamine-neurotrophic-factor-protect-against-and-rescue-neurodegeneration-of-pc12-cells
#14
Jia-Ming Mei, Chao-Shi Niu
Conserved dopamine neurotrophic factor protects and rescues dopaminergic neurodegeneration induced by 6-hydroxydopamine in vivo, but its potential value in treating Parkinson's disease remains controversial. Here, we used the proteasome inhibitors lactacystin and MG132 to induce neurodegeneration of PC12 cells. Afterwards, conserved dopamine neurotrophic factor was administrated as a therapeutic factor, both pretreatment and posttreatment. Our results showed that (1) conserved dopamine neurotrophic factor enhanced lactacystin/MG132-induced cell viability and morphology, and attenuated alpha-synuclein accumulation in differentiated PC12 cells...
July 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28841377/role-of-sporadic-parkinson-disease-associated-mutations-a18t-and-a29s-in-enhanced-alpha-synuclein-fibrillation-and-cytotoxicity
#15
Sanjay Kumar, Deepak Kumar Jangir, Roshan Kumar, Manisha Kumari, Neel Bhavesh, Tushar Kanti Maiti
Deposition of pre-synaptic protein α-synuclein in Lewy bodies and Lewy neurites in the substantia nigra region of brain has been linked with the clinical symptoms of the Parkinson's disease (PD). Proteotoxic stress conditions and mutations that cause abnormal aggregation of α-synuclein have close association with onset of PD and its progression. Therefore, studies pertaining to α-synuclein mutations play important roles in mechanistic understanding of aggregation behaviour of the protein and subsequent pathology...
August 25, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28835999/glucocerebrosidase-expression-patterns-in-the-non-human-primate-brain
#16
Iria G Dopeso-Reyes, Diego Sucunza, Alberto J Rico, Diego Pignataro, David Marín-Ramos, Elvira Roda, Ana I Rodríguez-Pérez, José L Labandeira-García, José L Lanciego
Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene. Mutations in GBA1 gene lead to Gaucher's disease, the most prevalent lysosomal storage disorder. GBA1 mutations reduce GCase activity, therefore promoting the aggregation of alpha-synuclein, a common neuropathological finding underlying Parkinson's disease (PD) and dementia with Lewy bodies. However, it is also worth noting that a direct link between GBA1 mutations and alpha-synuclein aggregation indicating cause and effect is still lacking, with limited experimental evidence to date...
August 23, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28827536/cellular-internalization-of-alpha-synuclein-aggregates-by-cell-surface-heparan-sulfate-depends-on-aggregate-conformation-and-cell-type
#17
Elisabet Ihse, Hodaka Yamakado, Xander M van Wijk, Roger Lawrence, Jeffrey D Esko, Eliezer Masliah
Amyloid aggregates found in the brain of patients with neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are thought to spread to increasingly larger areas of the brain through a prion-like seeding mechanism. Not much is known about which cell surface receptors may be involved in the cell-to-cell transfer, but proteoglycans are of interest due to their well-known propensity to interact with amyloid aggregates. In this study, we investigated the involvement of plasma membrane-bound heparan and chondroitin sulfate proteoglycans in cellular uptake of aggregates consisting of α-synuclein, a protein forming amyloid aggregates in Parkinson's disease...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28826526/small-molecule-pet-tracers-for-imaging-proteinopathies
#18
REVIEW
Chester A Mathis, Brian J Lopresti, Milos D Ikonomovic, William E Klunk
In this chapter, we provide a review of the challenges and advances in developing successful PET imaging agents for 3 major types of aggregated amyloid proteins: amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn). These 3 amyloids are involved in the pathogenesis of a variety of neurodegenerative diseases, referred to as proteinopathies or proteopathies, that include Alzheimer disease, Lewy body dementias, multiple system atrophy, and frontotemporal dementias, among others. In the Introduction section, we briefly discuss the history of amyloid in neurodegenerative diseases and describe why progress in developing effective imaging agents has been hampered by the failure of crystallography to provide definitive ligand-protein interactions for rational radioligand design efforts...
September 2017: Seminars in Nuclear Medicine
https://www.readbyqxmd.com/read/28821274/candidate-inflammatory-biomarkers-display-unique-relationships-with-alpha-synuclein-and-correlate-with-measures-of-disease-severity-in-subjects-with-parkinson-s-disease
#19
Lori N Eidson, George T Kannarkat, Christopher J Barnum, Jianjun Chang, Jaegwon Chung, Chelsea Caspell-Garcia, Peggy Taylor, Brit Mollenhauer, Michael G Schlossmacher, Larry Ereshefsky, Mark Yen, Catherine Kopil, Mark Frasier, Kenneth Marek, Vicki S Hertzberg, Malú G Tansey
BACKGROUND: Efforts to identify fluid biomarkers of Parkinson's disease (PD) have intensified in the last decade. As the role of inflammation in PD pathophysiology becomes increasingly recognized, investigators aim to define inflammatory signatures to help elucidate underlying mechanisms of disease pathogenesis and aid in identification of patients with inflammatory endophenotypes that could benefit from immunomodulatory interventions. However, discordant results in the literature and a lack of information regarding the stability of inflammatory factors over a 24-h period have hampered progress...
August 18, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28811225/alpha-synuclein-ferrireductase-activity-is-detectible-in-vivo-is-altered-in-parkinson-s-disease-and-increases-the-neurotoxicity-of-dopal
#20
Jennifer S McDowall, Ioanna Ntai, Kevin C Honeychurch, John P Hart, Philippe Colin, Bernard L Schneider, David R Brown
The normal cellular role of α-synuclein is of potential importance in understanding diseases in which an aggregated form of the protein has been implicated. A potential loss or change in the normal function of α-synuclein could play a role in the aetiology of diseases such as Parkinson's disease. Recently, it has been suggested that α-synuclein could cause the enzymatic reduction of iron and a cellular increase in Fe(II) levels. Experiments were carried out to determine if such activity could be measured in vivo...
August 12, 2017: Molecular and Cellular Neurosciences
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