Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a‐synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with ...Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019: Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.
This article is related to the Special Issue Synuclein which was solicited from the Synuclein Meeting 2019. Every 2 years for about 12 years, the Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. Alpha‐synuclein (aSyn) is implicated in several neurodegenerative disorders of the brain and in this review we cover various aspects of aSyn biology and pathobiology, as depicted in the various circles.
This article is related to the Special Issue "Synuclein"
Parkinson's disease (PD) is associated with the accumulation of alpha‐synuclein (aSyn) in intracellular inclusions known as Lewy bodies and Lewy neurites. Under physiological conditions, aSyn is ...found at the presynaptic terminal and exists in a dynamic equilibrium between soluble, membrane‐associated and aggregated forms. Emerging evidence suggests that, under pathological conditions, aSyn begins to accumulate and acquire a toxic function at the synapse, impairing their normal function and connectivity. However, the precise molecular mechanisms linking aSyn accumulation and synaptic dysfunction are still elusive. Here, we provide an overview of our current findings and discuss the hypothesis that certain aSyn aggregates may interact with proteins with whom aSyn normally does not interact with, thereby trapping them and preventing them from performing their normal functions in the cell. We posit that such abnormal interactions start to occur during the prodromal stages of PD, eventually resulting in the overt manifestation of clinical features. Therefore, understanding the nature and behaviour of toxic aSyn species and their contribution to aSyn‐mediated toxicity is crucial for the development of therapeutic strategies capable of modifying disease progression in PD and other synucleinopathies.
Alpha‐synuclein (aSyn) begins to accumulate and acquire a toxic function at the synapse, impairing its normal function and connectivity. aSyn aggregates may interact with proteins with whom aSyn normally does not interact with, thereby trapping them and preventing them from performing their normal function and, thereby, destabilizing the normal neuronal physiology. Such abnormal interactions start to occur during the prodromal stages of Parkinson's disease, eventually resulting in the overt manifestation of clinical features.
Background: Alpha-synuclein (aSyn) is a key player in neurodegenerative diseases such as Parkinson’s disease (PD), dementia with Lewy bodies, or multiple system atrophy. aSyn is expressed throughout ...the brain, and can also be detected in various peripheral tissues. In fact, initial symptoms of PD are non-motoric and include autonomic dysfunction, suggesting that the periphery might play an important role in early development of the disease. aSyn is expressed at relatively low levels in non-central tissues, which brings challenges for its detection and quantification in different tissues. Objective: Our goal was to assess the sensitivity of aSyn detection in central and peripheral mouse tissues through capillary electrophoresis (CE) immunoblot, considering the traditional SDS-PAGE immunoblot as the current standard. Methods: Tissues from central and non-central origin from wild type mice were extracted, and included midbrain, inner ear, and esophagus/stomach. aSyn detection was assessed through immunoblotting using Simple Western size-based CE and SDS-PAGE. Results: CE immunoblots show a consistent detection of aSyn in central and peripheral tissues. Through SDS-PAGE, immunoblots revealed a reliable signal corresponding to aSyn, particularly following membrane fixation. Conclusion: Our results suggest a reliable detection of aSyn in central and peripheral tissues using the CE Simple Western immunoblot system. These observations can serve as preliminary datasets when aiming to formally compare CE with SDS-PAGE, as well as for further characterization of aSyn using this technique.
The aim of this study was to investigate the prebiotic potential of pectin hydrolysates that were extracted from agroindustrial waste (apple pomace—AP and passion fruit peel—PFP) and were added to ...the diet of silver catfish (Rhamdia quelen). A 49‐day biological assay was conducted, and five test diets were evaluated: one diet was a control diet and the other four diets included pectin hydrolysates (2.5 and 5 g/kg). At 49 experimental days, biometric data and biological material were collected to determine the performance, plasma and liver and histological parameters and to evaluate the intestinal contents. The results were analysed by the normality test, which was followed by an analysis of the variance; the treatment means were compared by an orthogonal contrast analysis at a 5% level of significance. The inclusion of 2.5 g/kg apple pomace hydrolysates resulted in a greater production of butyric acid, increased thickness of the muscular layer and higher goblet cell count in the intestine. The inclusion of 5 g/kg apple pomace hydrolysates led to a greater concentration of liver protein. Further studies are needed to increase the knowledge about the use of these additives in the diet of silver catfish and to establish levels that allow greater gains for the species.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
•E2 and Gen increased plasma vitellogenin and E2 increased plasma mineral levels.•TRAP and ALP activities and transcript expression was modified by E2 and Gen.•Scales and liver express a different ...repertoire of nuclear/membrane estrogen receptors.•E2 and Gen induced similar gene expression changes in scales and in liver.•Regulation of E2 receptors and responsive gene expression was tissue-specific.
As in mammals, estrogens in fish are essential for reproduction but also important regulators of mineral homeostasis. Fish scales are a non-conventional target tissue responsive to estradiol and constitute a good model to study mineralized tissues effects and mechanisms of action of estrogenic compounds, including phytoestrogens. The responsiveness to estradiol and the phytoestrogen genistein, was compared between the scales and the liver, a classical estrogenic target, in sea bass (Dicentrarchus labrax). Injection with estradiol and genistein significantly increased circulating vitellogenin (for both compounds) and mineral levels (estradiol only) and genistein also significantly increased scale enzymatic activities suggesting it increased mineral turnover. The repertoire, abundance and estrogenic regulation of nuclear estrogen receptors (ESR1, 2a and 2b) and membrane G-protein receptors (GPER and GPER-like) were different between liver and scales, which presumably explains the tissue-specific changes detected in estrogen-responsive gene expression. In scales changes in gene expression mainly consisted of small rapid increases, while in liver strong, sustained increases/decreases in gene expression occurred. Similar but not overlapping gene expression changes were observed in response to both estradiol and genistein. This study demonstrates for the first time the expression of membrane estrogen receptors in scales and that estrogens and phytoestrogens, to which fish may be exposed in the wild or in aquaculture, both affect liver and mineralized tissues in a tissue-specific manner.
A wide range of estrogenic endocrine disruptors (EDCs) are accumulating in the environment and may disrupt the physiology of aquatic organisms. The effects of EDCs on fish have mainly been assessed ...using reproductive endpoints and in vivo animal experiments. We used a simple non-invasive assay to evaluate the impact of estrogens and EDCs on sea bass (Dicentrarchus labrax) and tilapia (Oreochromis mossambicus) scales. These were exposed to estradiol (E2), two phytoestrogens and six anthropogenic estrogenic/anti-estrogenic EDCs and activities of enzymes related to mineralized tissue turnover (TRAP, tartrate-resistant acid phosphatase and ALP, alkaline phosphatase) were measured. Semi-quantitative RT-PCR detected the expression of both membrane and nuclear estrogen receptors in the scales of both species, confirming scales as a target for E2 and EDCs through different mechanisms. Changes in TRAP or ALP activities after 30minute and 24h exposure were detected in sea bass and tilapia scales treated with E2 and three EDCs, although compound-, time- and dose-specific responses were observed for the two species. These results support again that the mineralized tissue turnover of fish is regulated by estrogens and reveals that the scales are a mineralized estrogen-responsive tissue that may be affected by some EDCs. The significance of these effects for whole animal physiology needs to be further explored. The in vitro fish scale bioassay is a promising non-invasive screening tool for E2 and EDCs effects, although the low sensitivity of TRAP/ALP quantification limits their utility and indicates that alternative endpoints are required.
•The relationship between dialysis dose and cytokines in hemodialysis was investigated.•The chemokine CXCL-10 was closed correlated to adequate and inadequate dialysis dose.•IL-10 was positively and ...CXCL-10 was negatively correlated to creatinine clearance.•Dialysis dose and creatinine were predictive of inflammatory overload in hemodialysis.•Inflammatory stress was revealed by multiple cytokines, especially IL-10 and CXCL-10.
Although the clearance of low-molecular weight toxins is modulated by dialysis dose, the relationship between dialysis adequacy and middle systemic inflammatory mediators is often overlooked. Thus, the relationship between dialysis adequacy, pro- and anti-inflammatory cytokines and chemokines in hemodialysis (HD) patients was investigated. Forty-eight HD patients (19 women and 25 men) were investigated. Age, body mass index, time in HD, nutritional status, Kt/V and blood biochemical parameters was similar in patients of both sexes (P > 0.05). Thus, patients were stratified by dialysis adequacy measured by Kt/V method (adequate Kt/V ≥ 1.2). Post-HD urea, creatinine, cytokines (IFN-γ, IL-4 and IL-10) and chemokines (CCL-2, CCL-5, CXCL-8 and CXCL-10) were higher in patients with Kt/V < 1.2 (P < 0.05). Kt/V exhibited significant correlation with CXCL-10/IP-10 serum levels. Positive correlation between creatinine with IFN-γ, CCL-2/MCP-1, and CXCL-10/IP-10, and negative correlation with IL-10 was identified in patients with Kt/V < 1.2 (P < 0.05). In patients with Kt/V ≥ 1.2, only IL-10 was positively and CXCL-10/IP-10 negatively correlated with creatinine levels (P < 0.05). Kt/V and creatinine levels exhibited variable predictive value (Kt/V = 27% to 37%, creatinine = 29% to 47%) to explain cytokines and chemokines circulating levels in patients with adequate and inadequate dialysis dose. Taken together, our findings provide evidence that in addition to modulating uremic toxins levels, such as urea and creatinine, dialysis dose is associated with circulating levels of inflammatory mediators. Thus, low Kt/V results and creatinine accumulation are potential indicators of the systemic inflammatory stress determined by up-regulation of proinflammatory cytokines and chemokines, and downregulation of anti-inflammatory cytokines.
Teleost fish skin-scales are essential for protection and homeostasis and the largest tissue in direct contact with the environment, but their potential as early indicators of pollutant exposure are ...hampered by limited knowledge about this model. This study evaluated multi-level impacts of in vivo exposure of European sea bass to fluoxetine (FLX, a selective serotonin-reuptake inhibitor and an emerging pollutant) and 17β-estradiol (E2, a natural hormone and representative of diverse estrogenic endocrine-disrupting pollutants). Exposed fish had significantly increased circulating levels of FLX and its active metabolite nor-FLX that, in contrast to E2, did not have estrogenic effects on most fish plasma and scale indicators. Quantitative proteomics using SWATH-MS identified 985 proteins in the scale total proteome. 213 proteins were significantly modified 5 days after exposure to E2 or FLX and 31 were common to both treatments and responded in the same way. Common biological processes significantly affected by both treatments were protein turnover and cytoskeleton reorganization. E2 specifically up-regulated proteins related to protein production and degradation and down-regulated the cytoskeleton/extracellular matrix and innate immune proteins. FLX caused both up- and down-regulation of protein synthesis and energy metabolism. Multiple estrogen and serotonin receptor and transporter transcripts were altered in sea bass scales after E2 and/or FLX exposure, revealing complex disruptive effects in estrogen/serotonin responsiveness, which may account for the partially overlapping effects of E2 and FLX on the proteome. A large number (103) of FLX-specifically regulated proteins indicated numerous actions independent of estrogen signalling. This study provides the first quantitative proteome of the fish skin-scale barrier, elucidates routes of action and biochemical and molecular signatures of E2 or FLX-exposure and identifies potential physiological consequences and candidate biomarkers of pollutant exposure, for monitoring and risk assessment.
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•Fish metabolise FLX into nor-FLX.•Scale SWATH proteomic signatures reveal 213 proteins are modified by E2/FLX.•E2/FLX impacts are linked to protein/matrix turnover and immune-related proteins.•Scale proteomic signatures of FLX partially overlap with E2.•E2/FLX regulate scale E2/serotonin receptors and transporters.
•NMR and multivariate analysis measure metabolic impact of lettuce growth and mancozeb exposure.•Expanded leaves show Krebs cycle and anti-oxidant defence mechanisms activation.•Mancozeb exposure ...leads to marked disturbances in amino acid and other metabolisms.•Mancozeb exposure emphasises activated Krebs cycle and anti-oxidant defence mechanisms.
This paper describes a proton high resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) metabolomic study of lettuce (Lactuca sativa L.) leaves to characterise metabolic adaptations during leaf growth and exposure to mancozeb. Metabolite variations were identified through multivariate analysis and checked through spectral integration. Lettuce growth was accompanied by activation of energetic metabolism, preferential glucose use and changes in amino acids, phospholipids, ascorbate, nucleotides and nicotinate/nicotinamide. Phenylalanine and polyphenolic variations suggested higher oxidative stress at later growth stages. Exposure to mancozeb induced changes in amino acids, fumarate and malate, suggesting Krebs cycle up-regulation. In tandem disturbances in sugar, phospholipid, nucleotide and nicotinate/nicotinamide metabolism were noted. Additional changes in phenylalanine, dehydroascorbate, tartrate and formate were consistent with a higher demand for anti-oxidant defence mechanisms. Overall, lettuce exposure to mancozeb was shown to have a significant impact on plant metabolism, with mature leaves tending to be more extensively affected than younger leaves.
•Advanced glycosylation end products (AGE) was investigated in hemodialysis (HD).•Cytokines, chemokines and oxidant markers was investigated in HD patients.•AGE, cytokines, chemokines and oxidant ...markers were correlated in HD patients.•AGE accumulation was relevant in predicting cytokines and chemokines in HD patients.•AGE accumulation was relevant in predicting oxidative damage in HD patients.
Controlling systemic proinflammatory and prooxidant effectors is essential for mitigating cardiovascular risk and mortality in patients with end-stage renal disease (ESRD). However, monitoring these processes is still challenging due to the high uncertainty about their determinants and predictors. Thus, we investigated the relationship between advanced glycosylation end products (AGE), proinflammatory and prooxidant effectors in ESRD patients undergoing hemodialysis (HD). In addition to nutritional profile and dialysis efficiency, AGE, cytokines, chemokines, C-reactive protein (CRP), total (TAC) and non-protein (npAC) antioxidant capacity, lipid and protein oxidation were analyzed in blood samples from 43 HD patients. AGE, CRP, cytokines, chemokines, protein carbonyl (PCn), and malondialdehyde (MDA) were upregulated, while TAC and npAC were down-regulated in HD patients compared to heath subjects. Dialysis efficiency, TAC and npAC were reduced, while leucocytes counting, pre- and post-HD urea, TNF, IL-6, IL-10, CCL-2, MIP-1β, PCn, and MDA were increased in patients with higher AGE accumulation compared to those with lower AGE levels. Serum levels of CRP, protein carbonyl, malondialdehyde, and all cytokines and chemokines analyzed were correlated with AGE circulating levels for patients with higher AGE accumulation. AGE was inversely correlated with IL-10, TAC and npAC in patients with higher AGE accumulation. AGE exhibited predictive value (determination coefficient) to explain CRP, cytokines, chemokines, PCN, MDA, TAC and npAC variability in patients with higher AGE levels. Taken together, our findings provide evidence that AGE accumulation is associated with important proinflammatory and prooxidant effectors in patients with ESRD undergoing hemodialysis. Thus, AGE monitoring may be relevant to predict systemic inflammatory stress and the balance between oxidant and antioxidant status in these patients.
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