1,720,966 research outputs found
Mitochondrial axonal transport in vivo: development of a new assay in zebrafish to study the effects of Familial Alzheimerâs Disease Presenilin 2 mutations
Full text linkAlzheimer's disease (AD) is the most common form of neurodegenerative disease, affecting more than 35 million people worldwide. Although the majority of cases is caused by a combination of risk factors (genetic and environmental), a small percentage is genetically inherited and is called familial Alzheimer's disease (FAD). FAD is caused by mutations in three genes: APP, which encodes for the amyloid precursor protein, and presenilins genes (PSEN1 and PSEN2), encoding for presenilin 1 and 2 (PS1, PS2), respectively. Mutations in these genes result in an increased formation of the product of APP cleavage, the amyloid Aβ peptide: in AD the levels of Aβ42, the most aggregation-prone, 42 amino acids long, form of Aβ, are increased, leading to the formation of amyloid plaques in patients' brains. According to the "amyloid hypothesis", Aβ accumulation triggers a cascade that leads to progressive synaptic and neuronal injury and eventually to cell death.
In this scenario, presenilins play a key role. Presenilins are membrane spanning proteins known to most as key components of the γ-secretase, the enzymatic complex located in plasma membrane and internal membranes (Golgi and endoplasmic reticulum, ER) responsible for the cleavage of many proteins, including NOTCH and APP. However, they also have γ-secretase-independent functions: in particular PS2, but not PS1, has been recently described to be able to modulate ER-mitochondria tethering and their Ca2+ cross-talk. The overexpression of FAD-linked PS2 mutants increases both the tethering and the Ca2+ transfer between these two organelles. Itâs worth mentioning that alterations in Ca2+ signalling are emerging as an attractive hypothesis to explain AD pathogenesis: many cellular processes are dependent on a proper Ca2+ signalling, and any dysfunction is expected to have consequences on neuronal physiology. Among these processes, mitochondrial axonal transport represents a very interesting feature: mitochondria are key organelles for cells, whose functions influence several cell life aspects as well as cell death. Mitochondrial axonal transport is finely regulated by Ca2+: increases in cytosolic Ca2+ levels arrest mitochondrial movements along axons, to ensure their deliver to metabolically active sites, such as activated synapses. The previously described FAD-PS2 mediated alterations in Ca2+ handling and in the physical interaction between ER and mitochondria could potentially modify axonal mitochondrial transport, and an altered mitochondrial distribution has been reported within neuronal cells in different AD models.
Zebrafish has emerged as an attractive vertebrate system to study human diseases: in particular, its genome is extensively annotated and orthologs of genes involved in FAD have been already identified. Mitochondrial axonal transport analysis is strongly facilitated by the transparency of embryos and by the availability of tools to manipulate gene expression.
We here generated a method to study PS2-dependent effects on mitochondrial dynamics in vivo. Firstly, by genetically targeting the fluorescent protein Kaede to mitochondria in Rohon-Beard (RB) sensory neurons, we have characterized mitochondrial axonal transport properties during development. We found that the percentage of mobile mitochondria is reduced from one to three days post fertilization (dpf) embryos; mitochondrial average speed, however, increases during development. The directionality of transport is strongly biased towards the anterograde one, reflecting a net translocation of mitochondria from the cell body to peripheral arbors. Nocodazole, a strong inhibitor of microtubule polymerization, totally disrupts mitochondrial axonal transport, validating the sensitivity of our assay. Interestingly, the mitochondrial axonal transport parameters, measured with our approach, are similar to those reported in recent in vivo studies.
We found that psen2 knockdown (KD), but not psen1 KD, reduces the percentage of motile organelles, compared to controls. This phenotype is recovered by rescue experiments, in which PS2 was re-introduced, demonstrating a specific PS2-dependent effect.
On the other side, human PS2 expression in zebrafish leads to different results: human PS2 (both wild-type, wt, and mutated) is expressed at the level of intracellular membranes (mainly in the ER) in the soma and through the axon of RB neurons but, while overexpression of wt PS2 does not affect mitochondrial axonal transport, that of the PS2-T122R mutant increases the percentage of motile mitochondria.
Moreover, we verified whether intra-mitochondrial Ca2+ rises could be involved as signal in the regulation of mitochondrial axonal transport, as previously proposed: the KD of the mitochondrial calcium uniporter (Mcu), the protein responsible for mitochondrial Ca2+ uptake, however, is without effect on either the speed and the percentage of motile mitochondria in RB neurons.
Mitochondrial morphology and density were also investigated and both features resulted unchanged upon the different treatments, suggesting that the observed alterations in mitochondrial axonal transport induced by PS2 are due to neither an imbalance in mitochondrial fusion and fission nor an abnormal mitochondrial biogenesis.
Further investigations are required to better understand the mechanism through which PS2 alters mitochondrial axonal transport, as well as the role played by this alteration in AD pathogenesis
Emerging (and converging) pathways in Parkinson's disease: keeping mitochondrial wellness
No full textThe selective cell loss in the ventral component of the substantia nigra pars compacta and the presence of alpha-synuclein (α-syn)-rich intraneuronal inclusions called Lewy bodies are the pathological hallmarks of Parkinson's disease (PD), the most common motor system disorder whose aetiology remains largely elusive. Although most cases of PD are idiopathic, there are rare familial forms of the disease that can be traced to single gene mutations that follow Mendelian inheritance pattern. The study of several nuclear encoded proteins whose mutations are linked to the development of autosomal recessive and dominant forms of familial PD enhanced our understanding of biochemical and cellular mechanisms contributing to the disease and suggested that many signs of neurodegeneration result from compromised mitochondrial function. Here we present an overview of the current understanding of PD-related mitochondrial dysfunction including defects in bioenergetics and Ca(2+) homeostasis, mitochondrial DNA mutations, altered mitochondrial dynamics and autophagy. We emphasize, in particular, the convergence of many "apparently" different pathways towards a common route involving mitochondria. Understanding whether mitochondrial dysfunction in PD represents the cause or the consequence of the disease is challenging and will help to define the pathogenic processes at the basis of the PD onset and progression
The Close Encounter Between Alpha-Synuclein and Mitochondria
No full textThe presynaptic protein alpha-synuclein (α-syn) is unequivocally linked to the development of Parkinson’s disease (PD). Not only it is the major component of amyloid fibrils found in Lewy bodies but mutations and duplication/triplication in its gene are responsible for the onset of familial autosomal dominant forms of PD. Nevertheless, the precise mechanisms leading to neuronal degeneration are not fully understood. Several lines of evidence suggest that impaired autophagy clearance and mitochondrial dysfunctions such as bioenergetics and calcium handling defects and alteration in mitochondrial morphology might play a pivotal role in the etiology and progression of PD, and indicate the intriguing possibility that α-syn could be involved in the control of mitochondrial function both in physiological and pathological conditions. In favor of this, it has been shown that a fraction of cellular α-syn can selectively localize to mitochondrial sub-compartments upon specific stimuli, highlighting possible novel routes for α-syn action. A plethora of mitochondrial processes, including cytochrome c release, calcium homeostasis, control of mitochondrial membrane potential and ATP production, is directly influenced by α-syn. Eventually, α-syn localization within mitochondria may also account for its aggregation state, making the α-syn/mitochondria intimate relationship a potential key for the understanding of PD pathogenesis. Here, we will deeply survey the recent literature in the field by focusing our attention on the processes directly controlled by α-syn within mitochondrial sub-compartments and its potential partners providing possible hints for future therapeutic targets
Zebrafish Tg(hb9:MTS-Kaede): A new in vivo tool for studying the axonal movement of mitochondria
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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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