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Domenica Marchese, Teresa Botta-Orfila, Davide Cirillo, Juan Antonio Rodriguez, Carmen Maria Livi, Rubén Fernández-Santiago, Mario Ezquerra, Maria J Martí, Elias Bechara, Gian Gaetano Tartaglia
Recent evidence indicates a link between Parkinson's Disease (PD) and the expression of a-synuclein (SNCA) isoforms with different 3' untranslated regions (3'UTRs). Yet, the post-transcriptional mechanisms regulating SNCA expression are unknown. Using a large-scale in vitro /in silico screening we identified RNA-binding proteins (RBPs) that interact with SNCA 3' UTRs. We identified two RBPs, ELAVL1 and TIAR, that bind with high affinity to the most abundant and translationally active 3' UTR isoform (575 nt)...
December 15, 2017: Nucleic Acids Research
Vasilios C Constantinides, George P Paraskevas, Evangelia Emmanouilidou, Olga Petropoulou, Anastasia Bougea, Kostas Vekrellis, Ioannis Evdokimidis, Eleftherios Stamboulis, Elisabeth Kapaki
INTRODUCTION: Differential diagnosis of Parkinson-plus patients (PSP, CBD, MSA) and Parkinson's disease (PD) patients is often not straightforward, particularly in atypical cases or at the initial stages of the diseases. Classic CSF biomarkers (amyloid-beta - Aβ42, tau protein - τT and phosphorylated tau protein - τP-181) are established biomarkers in the diagnosis of Alzheimer's disease (AD). CSF a-synuclein (α-syn) has emerged as a promising biomarker in patients with Parkinsonism...
November 15, 2017: Journal of the Neurological Sciences
Rafael Ramis, Joaquín Ortega-Castro, Bartolomé Vilanova, Miquel Adrover, Juan Frau
The interactions between N-terminally acetylated α-synuclein and Cu(II) at several binding sites have been studied with DFT calculations, specifically with the M06 hybrid functional and the ωB97X-D DFT-D functional. In previous experimental studies, Cu(II) was shown to bind several α-synuclein residues, including Met1-Asp2 and His50, forming square planar coordination complexes. Also, it was determined that a low-affinity binding site exists in the C-terminal domain, centered on Asp121. However, in the N-terminally acetylated protein, present in vivo, the Met1 site is blocked...
August 3, 2017: Journal of Physical Chemistry. A
Q-B Lu, Z-F Zhu, H-P Zhang, W-F Luo
OBJECTIVE: In the gastrointestinal neural system, the emergence of Lewy Body (LB) is usually earlier than the clinical diagnosis of Parkinson (PD) motor symptoms. Therefore, this study is aimed to explore whether the LB in the gastrointestinal tract of prodromal PD patients. PATIENTS AND METHODS: 98 paraffin embedded tissue specimens from 57 PD patients were collected in the Second Affiliated Hospital of Soochow University archives, as well as 98 tissue specimens of 90 non-PD patients undergone surgical resection...
April 2017: European Review for Medical and Pharmacological Sciences
Alessandra Bonito-Oliva, Shahar Barbash, Thomas P Sakmar, W Vallen Graham
During amyloid fibril formation, amyloidogenic polypeptides misfold and self assemble into soluble pre-fibrillar aggregates, i.e., protofibrils, which elongate and mature into insoluble fibrillar aggregates. An emerging class of chaperones, chaperone-like amyloid binding proteins (CLABPs), has been shown to interfere with aggregation of particular misfolded amyloid peptides or proteins. We have discovered that the calcium-binding protein nuclebindin-1 (NUCB1) is a novel CLABP. We show that NUCB1 inhibits aggregation of islet-amyloid polypeptide associated with type 2 diabetes mellitus, a-synuclein associated with Parkinson's disease, transthyretin V30M mutant associated with familial amyloid polyneuropathy, and Aβ42 associated with Alzheimer's disease by stabilizing their respective protofibril intermediates...
February 21, 2017: Scientific Reports
Katrina Albert, Merja H Voutilainen, Andrii Domanskyi, Mikko Airavaara
Gene delivery using adeno-associated virus (AAV) vectors is a widely used method to transduce neurons in the brain, especially due to its safety, efficacy, and long-lasting expression. In addition, by varying AAV serotype, promotor, and titer, it is possible to affect the cell specificity of expression or the expression levels of the protein of interest. Dopamine neurons in the substantia nigra projecting to the striatum, comprising the nigrostriatal pathway, are involved in movement control and degenerate in Parkinson's disease...
February 8, 2017: Genes
Liang Ouyang, Lan Zhang, Bo Liu
Parkinson's disease (PD) is a common neurodegenerative disorder associated with aging. Great progresses have been made toward understanding the pathogenesis over the past decades. It seems that both genetic factors and environmental factors contribute to PD, while the precise pathogenesis still remains unknown. Recently, increasing evidence has suggested that autophagy dysregulation is closely related to PD. Dysregulation of the autophagic pathways has been observed in the brains of PD patients or in animal models of PD, and a number of PD-associated proteins, such as a-synuclein, Parkin and PINK1, were found to involve in autophagy, suggesting a link between autophagy and pathogenesis of PD...
January 2016: Yao Xue Xue Bao, Acta Pharmaceutica Sinica
Andrei Surguchov
Parkinson's disease (PD) is a degenerative disorder of the central nervous system, in which a small naturally unfolded protein α-synuclein plays an essential role. α-Synuclein belongs to a synuclein family comprising three members: α, β, and γ-synucleins associated with neurodegenerative and neoplastic diseases and involved in development. Several studies revealed that α-synuclein is present not only in the brain, but also in the skin and other peripheral tissues. This finding open a new approach to PD diagnosis based on the assay of α-synuclein from a biological sample of a living patient...
2016: Brain Sciences
Shruti Sahay, Dhiman Ghosh, Pardeep K Singh, Samir K Maji
α-Synuclein (α-Syn) aggregation is directly associated with Parkinson's disease (PD) pathogenesis. In vitro aggregation and in vivo animal model studies of α-Syn recapitulate many features of the disease pathogenesis. Six familial PD associated mutations of α-Syn have been discovered; many of which are associated with early onset PD. Three of PD associated mutations have been shown to accelerate the α-Syn aggregation, whereas other three are shown to delay the aggregation kinetics. The membrane binding studies also suggest that few of these PD mutants strongly bind to synthetic membrane vesicles, while others are shown to have attenuated membrane binding ability...
2017: Current Protein & Peptide Science
Coralie Di Scala, Nouara Yahi, Alessandra Flores, Sonia Boutemeur, Nazim Kourdougli, Henri Chahinian, Jacques Fantini
Growing evidence supports a role for brain gangliosides in the pathogenesis of neurodegenerative diseases including Alzheimer's and Parkinson's. Recently we deciphered the ganglioside-recognition code controlling specific ganglioside binding to Alzheimer's β-amyloid (Aβ1-42) peptide and Parkinson's disease-associated protein α-synuclein. Cracking this code allowed us to engineer a short chimeric Aβ/α-synuclein peptide that recognizes all brain gangliosides. Here we show that ganglioside-deprived neural cells do no longer sustain the formation of zinc-sensitive amyloid pore channels induced by either Aβ1-42 or α-synuclein, as assessed by single-cell Ca(2+) fluorescence microscopy...
February 2016: Biochimica et Biophysica Acta
Clive Bate, Alun Williams
A key event in Alzheimer's disease (AD) is the production of amyloid-β (Aβ) peptides and the loss of synapses. In cultured neurons Aβ triggered synapse damage as measured by the loss of synaptic proteins. α-synuclein (αSN), aggregates of which accumulate in Parkinson's disease, also caused synapse damage. Synapse damage was associated with activation of cytoplasmic phospholipase A₂ (cPLA₂), an enzyme that regulates synapse function and structure, and the production of prostaglandin (PG) E₂. In synaptosomes PGE₂ increased concentrations of cyclic adenosine monophosphate (cAMP) which suppressed the activation of cPLA₂ demonstrating an inhibitory feedback system...
2015: Biology
Matthew E Gegg, Anthony H V Schapira
The lysosomal hydrolase glucocerebrosidase (GCase) is encoded for by the GBA gene. Homozygous GBA mutations cause Gaucher disease (GD), a lysosomal storage disorder. Furthermore, homozygous and heterozygous GBA mutations are numerically the greatest genetic risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. The loss of GCase activity results in impairment of the autophagy-lysosome pathway (ALP), which is required for the degradation of macromolecules and damaged organelles...
June 2016: Neurobiology of Disease
Parijat Kabiraj, Carlos A Valenzuela, Jose E Marin, David A Ramirez, Lois Mendez, Michael S Hwang, Armando Varela-Ramirez, Karine Fenelon, Mahesh Narayan, Rachid Skouta
Endoplasmic reticulum (ER) proteins including protein disulfide isomerase (PDI) are playing crucial roles in maintaining appropriate protein folding. Under nitrosative stress, an excess of nitric oxide (NO) radical species induced the S-nitrosylation of PDI cysteines which eliminate its isomerase and oxidoreductase capabilities. In addition, the S-nitrosylation-PDI complex is the cause of aggregation especially of the α-synuclein (α-syn) protein (accumulation of Lewy-body aggregates). We recently identified a potent antioxidant small molecule, Ferrostatin-1 (Fer-1), that was able to inhibit a non-apoptotic cell death named ferroptosis...
October 2015: Protein Journal
Robert Blum, Klaus-Peter Lesch
No abstract text is available yet for this article.
November 2015: Journal of Neurochemistry
Asuka Sasaki, Shigeki Arawaka, Hiroyasu Sato, Takeo Kato
α-Synuclein deposited in Lewy bodies, a pathological hallmark of Parkinson's disease (PD), is highly phosphorylated at serine 129 (Ser129). In contrast, there is very little Ser129-phosphorylated α-synuclein in the normal brains. This difference suggests that Ser129-phosphorylation is involved in neurodegenerative processes of PD. However, the role of this modification remains unclear. One limiting factor for relevant biochemical analyses is that it is difficult to detect endogenous Ser129-phosphorylated α-synuclein by western blotting, because α-synuclein monomers detached from the transferred membrane during incubation...
2015: Scientific Reports
Cristian Follmer, Eduardo Coelho-Cerqueira, Danilo Y Yatabe-Franco, Gabriel D T Araujo, Anderson S Pinheiro, Gilberto B Domont, David Eliezer
Oxidative deamination of dopamine produces the highly toxic aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL), enhanced production of which is found in post-mortem brains of Parkinson disease patients. When injected into the substantia nigra of rat brains, DOPAL causes the loss of dopaminergic neurons accompanied by the accumulation of potentially toxic oligomers of the presynaptic protein α-synuclein (aS), potentially explaining the synergistic toxicity described for dopamine metabolism and aS aggregation...
November 13, 2015: Journal of Biological Chemistry
Joe Kakish, Dongsoo Lee, Jeremy S Lee
The misfolding of α-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson's disease. Drugs that bind to α-synuclein and form a loop structure between the N- and C-terminus tend to be neuroprotective, whereas others that cause a more compact structure tend to be neurotoxic. The binding of several natural products and other drugs that are involved in dopamine metabolism were investigated by nanopore analysis and isothermal titration calorimetry. The antinausea drugs, cinnarizine and metoclopramide, do not bind to α-synuclein, whereas amphetamine and the herbicides, paraquat and rotenone, bind tightly and cause α-synuclein to adopt a more compact conformation...
December 16, 2015: ACS Chemical Neuroscience
Ting-Ting Du, Le Wang, Chun-Li Duan, Ling-Ling Lu, Jian-Liang Zhang, Ge Gao, Xiao-Bo Qiu, Xiao-Min Wang, Hui Yang
Loss-of-function mutations in the gene encoding GBA (glucocerebrosidase, β, acid), the enzyme deficient in the lysosomal storage disorder Gaucher disease, elevate the risk of Parkinson disease (PD), which is characterized by the misprocessing of SNCA/α-synuclein. However, the mechanistic link between GBA deficiency and SNCA accumulation remains poorly understood. In this study, we found that loss of GBA function resulted in increased levels of SNCA via inhibition of the autophagic pathway in SK-N-SH neuroblastoma cells, primary rat cortical neurons, or the rat striatum...
2015: Autophagy
Marcus Keatinge, Hai Bui, Aswin Menke, Yu-Chia Chen, Anna M Sokol, Qing Bai, Felix Ellett, Marc Da Costa, Derek Burke, Matthew Gegg, Lisa Trollope, Thomas Payne, Aimee McTighe, Heather Mortiboys, Sarah de Jager, Hugh Nuthall, Ming-Shang Kuo, Angeleen Fleming, Anthony H V Schapira, Stephen A Renshaw, J Robin Highley, Agnieszka Chacinska, Pertti Panula, Edward A Burton, Michael J O'Neill, Oliver Bandmann
Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1(+/-)) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1(+/-) carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA1(+/-) carriers...
December 1, 2015: Human Molecular Genetics
Anna Wilkaniec, Grzegorz A Czapski, Agata Adamczyk
Cyclin-dependent kinase 5 (Cdk5) is involved in proper neurodevelopment and brain function and serves as a switch between neuronal survival and death. Overactivation of Cdk5 is associated with many neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. It is believed that in those diseases Cdk5 may be an important link between disease-initiating factors and cell death effectors. A common hallmark of neurodegenerative disorders is incorrect folding of specific proteins, thus leading to their intra- and extracellular accumulation in the nervous system...
January 2016: Journal of Neurochemistry
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