1,720,974 research outputs found
The αSynuclein half-life conundrum
Full text linkalpha Synuclein (alpha Syn) misfolding and aggregation frequently precedes neuronal loss associated with Parkinson's Disease (PD) and other Synucleinopathies. The progressive buildup of pathological alpha Syn species results from alterations on alpha Syn gene and protein sequence, increased local concentrations, variations in alpha Syn interactome and protein network. Therefore, under physiological conditions, it is mandatory to regulate alpha Syn proteostasis as an equilibrium among synthesis, trafficking, degradation and extracellular release. In this frame, a crucial parameter is protein half-life. It provides indications of the turnover of a specific protein and depends on mRNA synthesis and translation regulation, subcellular localization, function and clearance by the designated degradative pathways. For alpha Syn, the molecular mechanisms regulating its proteostasis in neurons have been extensively investigated in various cellular models, either using biochemical or imaging approaches. Nevertheless, a converging estimate of alpha Syn half-life has not emerged yet. Here, we discuss the challenges in studying alpha Syn proteostasis under physiological and pathological conditions, the advantages and disadvantages of the experimental strategies proposed so far, and the relevance of determining alpha Syn half-life from a translational perspective
DOPAL-induced impairment of aSynuclein and cellular proteostasis as molecular mechanism to enhance neuronal vulnerability in Parkinson's disease.
Full text linkParkinson’s Disease (PD) is pathologically characterized by the progressive loss of nigrostriatal dopaminergic neurons and aberrant accumulation of the pre-synaptic protein aSynuclein (aSyn). Several factors have been proposed to trigger aSyn aggregation, resulting aSyn-induced neurotoxicity. Here, the working hypothesis is to assess how the interplay between aSyn and an altered dopamine metabolism may contribute to the pathogenesis of PD. A relevant role has been assigned to the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), whose neurotoxic action has been supported by several experimental models. Being an aldehyde, DOPAL covalently modifies lysine residues of proteins, thus aSyn is considered a preferential target due to the high percentage of lysines in its sequence, its unfolded state and abundance at synapses. In vitro and cellular studies demonstrated that DOPAL triggers aSyn oligomerization, prevents aSyn association to synaptic vesicle membranes and affects synapse physiology. Of note, some lysines on aSyn sequence that were identified as DOPAL-modified, are also reported as target of functional post-translational modifications that regulate aSyn proteostasis.
On this ground, we aimed to investigate the consequences of DOPAL build-up in neurons on both aSyn and cellular proteostasis, in a wider perspective. To address these issues, cellular biology and biochemical studies were coupled with advanced imaging techniques, like the correlated light and electron microscopy (CLEM), which allows to map the aSyn localization, both at cellular and supra-molecular level. As cellular models, we worked on both rat primary cortical neurons and the catecholaminergic BE(2)-M17 cells.
Here, we provided evidence of a DOPAL-dependent aSyn redistribution in the neuronal compartments, from the peripheral terminals to its axonal trafficking to the soma. These observations were also linked to the assessment of aSyn affected clearance in the presence of DOPAL. Interestingly, DOPAL appeared to promote the aSyn loading in the multi-vesicular bodies (MVBs) of the endosomal pathway and the aSyn accumulation within perinuclear lysosomes, both in its monomeric and oligomeric forms.
Since aSyn oligomers are known to affect protein degradation systems functionality, we aimed to unravel the hypothesis of a synergistic effect of aSyn and DOPAL on a general impairment of cellular proteostasis. Indeed, increasing concentrations of DOPAL treatment in BE(2)-M17 cells led to a dose-dependent accumulation of ubiquitinated proteins and the autophagic marker p62, suggesting a potential impairment of the proteasome and the autophagic flux, respectively.
Finally, we recently started to explore a translational approach to control DOPAL-associated toxicity. Specifically, we used biguanidine molecules as aldehyde scavengers, i.e. aminoguanidine and metformin, that are already in clinical practice. So far, preliminary experiments confirmed the ability of aminoguanidine to slow-down DOPAL-induced aSyn in vitro oligomerization. Also, both aminoguanidine and metformin treatments reduced the accumulation of p62 caused by DOPAL in BE(2)-M17. Given these promising results, the beneficial effect of these compounds against the DOPAL-associated neurotoxicity will be further investigated.
In conclusion, DOPAL build-up in the cellular environment causes impaired aSyn trafficking, aSyn aggregation and decreased clearance. At the same time, DOPAL appears to affect protein degradation systems functionality, which would result in overall impaired neuronal proteostasis. Finally, the DOPAL-induced overload in MVBs together with the blockage of autophagy might promote the secretion of DOPAL-modified aSyn through exosomes, spreading these toxic species in the surrounding environment. On this ground, a therapeutic approach to target DOPAL neurotoxicity on site and to promote protein turnover might be of interest.Parkinson’s Disease (PD) is pathologically characterized by the progressive loss of nigrostriatal dopaminergic neurons and aberrant accumulation of the pre-synaptic protein aSynuclein (aSyn). Several factors have been proposed to trigger aSyn aggregation, resulting aSyn-induced neurotoxicity. Here, the working hypothesis is to assess how the interplay between aSyn and an altered dopamine metabolism may contribute to the pathogenesis of PD. A relevant role has been assigned to the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), whose neurotoxic action has been supported by several experimental models. Being an aldehyde, DOPAL covalently modifies lysine residues of proteins, thus aSyn is considered a preferential target due to the high percentage of lysines in its sequence, its unfolded state and abundance at synapses. In vitro and cellular studies demonstrated that DOPAL triggers aSyn oligomerization, prevents aSyn association to synaptic vesicle membranes and affects synapse physiology. Of note, some lysines on aSyn sequence that were identified as DOPAL-modified, are also reported as target of functional post-translational modifications that regulate aSyn proteostasis.
On this ground, we aimed to investigate the consequences of DOPAL build-up in neurons on both aSyn and cellular proteostasis, in a wider perspective. To address these issues, cellular biology and biochemical studies were coupled with advanced imaging techniques, like the correlated light and electron microscopy (CLEM), which allows to map the aSyn localization, both at cellular and supra-molecular level. As cellular models, we worked on both rat primary cortical neurons and the catecholaminergic BE(2)-M17 cells.
Here, we provided evidence of a DOPAL-dependent aSyn redistribution in the neuronal compartments, from the peripheral terminals to its axonal trafficking to the soma. These observations were also linked to the assessment of aSyn affected clearance in the presence of DOPAL. Interestingly, DOPAL appeared to promote the aSyn loading in the multi-vesicular bodies (MVBs) of the endosomal pathway and the aSyn accumulation within perinuclear lysosomes, both in its monomeric and oligomeric forms.
Since aSyn oligomers are known to affect protein degradation systems functionality, we aimed to unravel the hypothesis of a synergistic effect of aSyn and DOPAL on a general impairment of cellular proteostasis. Indeed, increasing concentrations of DOPAL treatment in BE(2)-M17 cells led to a dose-dependent accumulation of ubiquitinated proteins and the autophagic marker p62, suggesting a potential impairment of the proteasome and the autophagic flux, respectively.
Finally, we recently started to explore a translational approach to control DOPAL-associated toxicity. Specifically, we used biguanidine molecules as aldehyde scavengers, i.e. aminoguanidine and metformin, that are already in clinical practice. So far, preliminary experiments confirmed the ability of aminoguanidine to slow-down DOPAL-induced aSyn in vitro oligomerization. Also, both aminoguanidine and metformin treatments reduced the accumulation of p62 caused by DOPAL in BE(2)-M17. Given these promising results, the beneficial effect of these compounds against the DOPAL-associated neurotoxicity will be further investigated.
In conclusion, DOPAL build-up in the cellular environment causes impaired aSyn trafficking, aSyn aggregation and decreased clearance. At the same time, DOPAL appears to affect protein degradation systems functionality, which would result in overall impaired neuronal proteostasis. Finally, the DOPAL-induced overload in MVBs together with the blockage of autophagy might promote the secretion of DOPAL-modified aSyn through exosomes, spreading these toxic species in the surrounding environment. On this ground, a therapeutic approach to target DOPAL neurotoxicity on site and to promote protein turnover might be of interest
Patients Stratification Strategies to Optimize the Effectiveness of Scavenging Biogenic Aldehydes: Towards a Neuroprotective Approach for Parkinson's Disease
No full textParkinson's disease (PD) is a clinically heterogeneous disorder with a multi-factorial pathology. Various molecular mechanisms are involved in the pathogenesis of PD, converging to oxidative stress and proteinopathy. The accumulation of reactive aldehydes (i.e., the dopamine metabolite DOPAL, lipid-peroxidation products, and advanced glycation end-products) has been reported in PD patients' brains. Aldehydes easily react with primary amines such as lysine residues, which are involved in several regulatory processes in cells. Therefore, aldehyde adducts lead to severe consequences, including neuronal proteostasis, mitochondrial dysfunction, and cell death. In this review, we analyzed the scavenging role of amines toward toxic aldehydes in the brain. Interestingly, small molecules like metformin, rasagiline, hydralazine are already clinically available and used in the therapy for PD and other diseases. Hence, we propose to reevaluate this class of drugs as a disease-modifiers for PD, and we suggest that improved analysis of their pharmacology and bioavailability in the brain, together with a more precise patients stratification, should be considered before planning future clinical trials
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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