1,721,083 research outputs found
Optimized adeno-associated vector to deliver the unfolded protein response transcription factor XBP1s into the hippocampus ameliorates Alzheimer’s disease features in mouse models
No full textProteostasis impairment at the level of the endoplasmic reticulum (ER) is a salient feature of Alzheimer’s disease (AD). The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER, where the expression of the transcription factor X-Box binding protein 1 (XBP1) is central to establish repair programs. To artificially enforce the adaptive capacity of the UPR in the AD brain, we recently reported the protective effects of overexpressing active XBP1 in the nervous system through the local delivery into the hippocampus of an AD mice using adeno-associated vectors (AAVs). Here we have generated a next generation vector suitable for clinical trials by (i) expressing codon optimized human XBP1s without tags, (ii) the use the synapsin promoter to restrict expression to neurons, and (iii) a novel variant of AAV2 that has greater spreading capacity (AAV-TT) in the brain because of reduced affinity to heparin (termed AAV-TT-Syn-hXBP1s or Proteostaser-1). Treatment of 5xFAD mice with AAV-TT-Syn-hXBP1s improved long-term potentiation, memory performance, and reduced amyloid plaques deposition. In addition, we validated the protective effects of AAV-TT-Syn-hXBP1s on a model of sporadic AD based on the intracerebral injection of amyloid beta oligomers. Our results further support the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function
Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.
No full textData used for Research Article submission to Molecular Therapy Journal for review Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting on a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress. Here we provide evidence of suboptimal activation of the UPR in ALS/FTD models under experimental ER stress. To artificially engage the UPR, we intracerebroventricularly administrated adeno-associated viruses (AAV) to express the active form of XBP1 (XBP1s) in the nervous system of ALS/FTD models. XBP1s expression improved motor performance and extended life span of mutant SOD1 mice, associated with reduced protein aggregation. AAV-XBP1s administration also attenuated disease progression in models of TDP-43 and C9orf72 pathogenesis. Proteomic profiling of spinal cord tissue revealed that XBP1s overexpression improved proteostasis and modulated the expression of a cluster of synaptic and cell morphology proteins. Our results suggest that strategies to improve ER proteostasis may serve as a pan-therapeutic strategy to treat ALS/FTD
Expression of a protein disulfide isomerase A3 variant associated to amyotrophic lateral sclerosis triggers disease features in mice
No full textAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motoneurons and compromised proteostasis. Dysfunction of the endoplasmic reticulum (ER) has been identified as a transversal pathogenic mechanism associated to motoneurons vulnerability in ALS. Protein disulfide isomerases (PDIs) are key enzymes catalyzing protein folding at the ER that are altered in the disease, involving both biochemical and genetic perturbations. We previously identified mutations in the gene encoding PDIA3 (also known as Grp58 or ERp57) in ALS cases, which were associated with altered neurite outgrowth in cell culture and abnormal motoneuron connectivity in zebrafish. Here we report the generation of transgenic mice expressing the ALS-associated PDIA3Q481K variant. Moderate PDIA3Q481K overexpression resulted in altered motor capacity accompanied by decreased motoneurons number and induction of ER stress in the spinal cord. The adverse effects of PDIA3Q481K were associated with altered electromyogram without evident morphological changes in neuromuscular junctions. Our results suggest that the PDIA3Q481K variant is pathogenic and its overexpression in mice recapitulate some ALS features, further supporting the concept that altered proteostasis due to PDI dysfunction constitute a risk factor to develop the disease
The unfolded protein response transcription factor XBP1s ameliorates Alzheimer’s disease by improving synaptic function and proteostasis
No full textAlteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer´s disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main signaling pathway emerging from the ER to cope with protein folding stress. Inositol requiring enzyme-1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a central ER stress sensor, enabling the establishment of adaptive programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). A polymorphism in the XBP1 promoter was suggested as a risk factor to develop AD. To artificially enforce the adaptive capacity of the UPR, here we developed strategies to express the active form of XBP1 in neurons on a preclinical model of AD. The overexpression of XBP1s in the nervous system using transgenic mice significantly reduced the load of amyloid deposition in cerebral cortex and hippocampus, in addition to preserve synaptic and cognitive function. Moreover, the local delivery of XBP1s in the hippocampus of AD mice using viral vectors improved long-term potentiation, memory performance and the density of dendritic spines. Quantitative proteomics of hippocampus indicated that XBP1 expression restores the levels of many synaptic protein and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of XBP1s-deppedent responses as a strategy to ameliorate AD features and sustain synaptic function
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
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