Plasma microRNAs (miRNAs) are promising biomarkers for several diseases. Our aim was to define the miRNA profile in plasma from Parkinson´s disease (PD) patients and healthy controls. We performed TaqMan low density arrays (TLDAs) in pools of patients and controls. Seven miRNAs differently expressed between the two groups were individually assayed in a total of 31 PD patients and 25 controls. remained significantly increased in patients vs. controls. A bioinformatic analysis predicted that this miRNA could be involved in the regulation of genes related with PD and brain function (axon guidance, MPK signaling pathway or insulin signaling pathway). We concluded that miR-331-5p could be a candidate plasma miRNA to be studied in PD related pathways. Plasma (circulating) miRNAs have been proposed as biomarkers for several diseases and ageing [9-10]. Our aim was to characterize the plasma miRNA profile in PD patients and healthy controls, to determine its usefulness as biomarkers for PD. The study was approved by the Ethical Committee of Hospital Universitario Central de Asturias (HUCA) and all the participants signed an informed consent. The study cohort consisted on sex and age matched healthy controls (n=25; mean age 67.6; 52% males) and patients (n=31; mean age 63.9; 55% males) who fulfilled the PD-clinical diagnosis criteria [11]. None of the patients was receiving drugs for PD-treatment or had a diagnosis of cardiovascular or tumor disease.
RNA is commonly believed to undergo a number of sequential folding steps before reaching its functional fold, i.e., the global minimum in the free energy landscape. However, there is accumulating evidence that several functional conformations are often in coexistence, corresponding to multiple (local) minima in the folding landscape. Here we use the 5′-exon-intron recognition duplex of a self-splicing ribozyme as a model system to study the influence of Mg 2+ NA folding is a hierarchical process that depends on the sequential formation of secondary and tertiary structures. As the RNA phosphate-sugar backbone is negatively charged, structural compaction creates electrostatic repulsion, which must be overcome by positive charges. The majority of negative charges are nonspecifically screened by the ion atmosphere, typically a set of dynamically exchanging M + ions (1). An estimated 10-20% of negative charge is, however, compensated by M n+ that bind site-specifically to the RNA molecule, in particular, Mg 2+ (2). One RNA molecule that is known to harbor several specific M 2+ binding sites is the self-splicing group II intron Sc.ai5γ from the yeast mitochondrial cox1 (cytochrome oxidase 1) gene (3). It is one of the largest known RNA enzymes, and both its folding pathway and catalysis are strictly dependent on Mg 2+. In turn, the splicing reaction is inhibited by small amounts of Ca 2+ (4). Site specificity of the two sequential transesterfication reactions is ensured by proper base pairing between distal exon-binding sites (5′ cleavage, EBS1 and 2; 3′ cleavage, EBS3) and intron-binding sites (IBS1, 2, and 3) (5).Single-molecule Förster resonance energy transfer (smFRET), i.e., distance-dependent energy transfer between a single pair of fluorophores, is ideally suited to study the cation-dependent conformational dynamics of single RNA molecules (6, 7). If different conformations lead to distinctly different transfer efficiencies, smFRET unveils the entire folding pathway, reports on the relative occurrence of all conformations present in the ensemble, and provides detailed information on the rates at which they interconvert (7). This is important because simple two-state folding is rarely observed in experimental data (8, 9). Rather, the vast conformational space sampled by biomolecules often results not only in folding intermediates but also in kinetic traps and/or multiple native states. In an smFRET experiment, individual molecules consequently display different behaviors that may or may not persist over the observation period (10). Heterogeneity has been precedented for a number of RNA molecules, including group I introns (11, 12), the hairpin ribozyme (13-17), and RNase P RNA (18). In addition, heterogeneity has been reported for different . However, the molecular basis of the phenomenon is often enigmatic, and its quantitative characterization is challenging (21).Here we use the 5′-exon-intron recognition site of the Sc.ai5γ ribozyme to study Mg 2+ -and Ca 2+ -mediated RNA-RNA structure formation by smFRET. ...
A class of rotaxane is created, not by encapsulating a conventional linear thread, but rather by wrapping a large cucurbit[10]uril macrocycle about a three-dimensional, cylindrical, nanosized, self-assembled supramolecular helicate as the axle. The resulting pseudo-rotaxane is readily converted into a proper interlocked rotaxane by adding branch points to the helicate strands that form the surface of the cylinder (like branches and roots on a tree trunk). The supramolecular cylinder that forms the axle is itself a member of a unique and remarkable class of helicate metallo-drugs that bind Y-shaped DNA junction structures and induce cell death. While pseudo-rotaxanation does not modify the DNA-binding properties, proper, mechanically-interlocked rotaxanation transforms the DNA-binding and biological activity of the cylinder. The ability of the cylinder to de-thread from the rotaxane (and thus to bind DNA junction structures) is controlled by the extent of branching: fully-branched cylinders are locked inside the cucurbit[10]uril macrocycle, while cylinders with incomplete branch points can de-thread from the rotaxane in response to competitor guests. The number of branch points can thus afford kinetic control over the drug de-threading and release.
The deregulation of several microRNAs (miRNAs) has been associated with neurodegenerative processes, including Parkinson's disease (PD). Our aim was to characterize the level of miRNAs in the substantia nigra (SN) of PD patients and healthy donors. This is an important issue to characterize new putative markers and therapeutic targets for PD. RNA was extracted from the SN of postmortem PD (n=8) and healthy (n=4) subjects, and the level of 733 human miRNAs was assayed with TaqMan low-density arrays (TLDAs). Overall, there was a miRNA downregulation in the SN of patients. The mean level of 11 miRNAs was significantly different (p<0.05) between patients and controls, with 10 downregulated among the patients. MiR-198, -135b, -485-5p, and -548d were the best candidates and were quantified with individual TaqMan assays in the 12 samples. MiR-135b showed the most significant difference between patients and healthy donors. The bioinformatic analysis suggested that this miRNA could bind to genes implicated in several neurodegenerative pathways.
The conjugation of arginine residues at the ends of a metallo-supramolecular triple-helical cylinder enables absolute control over the helicity of the cylinder core, and boosts the DNA junction recognition by the complexes and their activity against a cancer cell line.
Alpha-synuclein gene (SNCA) polymorphisms have been associated with the common sporadic form of Parkinson's disease (PD). We searched for DNA variants at the SNCA 3' UTR through single strand conformation analysis and direct sequencing in a cohort of Spanish PD patients and controls. We have genotyped the rs356165 SNCA 3' UTR polymorphism in a total of 1,135 PD patients and 772 healthy controls from two Spanish cohorts (Asturias and Navarre). We identified six SNCA 3' UTR variants. Single nucleotide polymorphism (SNP) rs356165 was significantly associated with PD risk in the Spanish cohort (p = 0.0001; odd ratio = 1.37, 95%CI = 1.19-1.58). This SNP was also significantly associated with early age at onset of PD. Our work highlights rs356165 as an important determinant of the risk of developing PD and early age at onset and encourages future research to identify a functional effect on SNCA expression.
MicroRNAs are small RNA sequences that negatively regulate gene expression by binding to the 3' untranslated regions of mRNAs. MiR-133b has been implicated in Parkinson's disease (PD) by a mechanism that involves the regulation of the transcription factor PITX3. The variation in these genes could contribute to the risk of developing PD. We searched for DNA variants in miR-133 and PITX3 genes in PD patients and healthy controls from Spain. We found common DNA variants in the three miR-133 genes. Genotyping of a first set of patients (n = 777) and controls (n = 650) showed a higher frequency of homozygous for a miR-133b variant (-90 del A) in PD-patients (6/575; 1%) than in healthy controls (0/650) (P = 0.03). However, this association was not confirmed in a second set of patients (1/250; 0.4%) and controls (2/210; 1%). No common PITX3 variants were associated with PD, although a rare missense change (G32S) was found in only one patient and none of the controls. In conclusion, we report the variation in genes of a pathway that has been involved in dopaminergic neuron differentiation and survival. Our work suggests that miR-133 and PITX3 gene variants did not contribute to the risk for PD.
Polymorphisms at genes encoding proteins involved in the pathogenesis of psoriasis (Psor) or in the mechanism of action of biological drugs could influence the treatment response. Because the interleukin (IL)-17 family has a central role in the pathogenesis of Psor, we hypothesized that IL17RA variants could influence the response to anti-TNF drugs among Psor patients. To address this issue we performed a cross-sectional study of Psor patients who received the biological treatments for the first time, with a follow-up of at least 6 months. All of the patients were Caucasian, older than 18 years old, with chronic plaque Psor, and had completed at least 24 weeks of anti-TNF therapy (adalimumab, etanercept or infliximab). The treatment response to anti-TNF agents was evaluated according to the achievement of PASI50 and PASI75 at weeks 12 and 24. Those who achieved PASI75 at week 24 were considered good responders. All patients were genotyped for the selected single-nucleotide polymorphisms (SNPs) at IL17RA gene. A total of 238 patients were included (57% male, mean age 46 years). One hundred and five patients received adalimumab, 91 patients etanercept and 42 infliximab. The rs4819554 promoter SNP allele A was significantly more common among responders at weeks 12 (P=0.01) and 24 (P=0.04). We found a higher frequency of AA versus AG+GG among responders, but the difference was only significant at week 12 (P=0.03, odd ratio=1.86, 95% confidence of interval=1.05-3.27). Thus, in the study population, the SNP rs4819554 in the promoter region of IL17RA significantly influences the response to anti-TNF drugs at week 12.
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