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Search Results: 1 - 10 of 10897 matches for " Pierre Rustin "
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Friedreich's Ataxia, Frataxin, PIP5K1B: Echo of a Distant Fracas
Aurélien Bayot,Pierre Rustin
Oxidative Medicine and Cellular Longevity , 2013, DOI: 10.1155/2013/725635
Abstract: “Frataxin fracas” were the words used when referring to the frataxin-encoding gene (FXN) burst in as a motive to disqualify an alternative candidate gene, PIP5K1B, as an actor in Friedreich's ataxia (FRDA) (Campuzano et al., 1996; Cossee et al., 1997; Carvajal et al., 1996). The instrumental role in the disease of large triplet expansions in the first intron of FXN has been thereafter fully confirmed, and this no longer suffers any dispute (Koeppen, 2011). On the other hand, a recent study suggests that the consequences of these large expansions in FXN are wider than previously thought and that the expression of surrounding genes, including PIP5K1B, could be concurrently modulated by these large expansions (Bayot et al., 2013). This recent observation raises a number of important and yet unanswered questions for scientists and clinicians working on FRDA; these questions are the substratum of this paper. 1. Friedreich’s Ataxia With an estimated prevalence of 1?:?50,000 and a carrier frequency of about 1?:?60 to 1?:?90, Friedreich’s ataxia (FRDA) is the most commonly inherited ataxia in the Caucasian population [1, 2]. It is a multisystemic, degenerative disease typically associated with dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, loss of position and vibration sense, and speech and listening difficulties [3]. A majority of the affected individuals have hypertrophic cardiomyopathy. Glucose intolerance and diabetes mellitus are observed in a subset (about 30%) of cases. The onset of symptoms is usually between 10 and 15 years of age, but either much earlier or later onset has been infrequently observed. Initial symptoms can be purely neurological, but occasionally, cardiomyopathy can be the presenting symptom. Altogether, atypical presentations represent as much as 25% of the cases [4]. 2. The Molecular Mechanism In more than 98% of the cases, the disease originates from large homozygous GAA repeat expansions (66 to 1700 repeats; normal: 5 to 33, with 85% less than 12) in the first intron of FXN encoding a mitochondrial matrix targeted protein, frataxin. In between uninterrupted expansions, 34 to 66 represent premutation, or borderline alleles, at risk for intergenerational expansion. The few residual cases represent compound heterozygous for an expanded allele and a point mutation, most frequently a null mutation [5]. 3. Frataxin Depletion: Iron-Sulfur Cluster Deficiency Simultaneously to the discovery of the molecular basis of FRDA by the European consortium combining the teams
Deferiprone targets aconitase: Implication for Friedreich's ataxia treatment
Sergio Goncalves, Vincent Paupe, Emmanuel P Dassa, Pierre Rustin
BMC Neurology , 2008, DOI: 10.1186/1471-2377-8-20
Abstract: Control and Friedreich's ataxia patient cultured skin fibroblasts, frataxin-depleted neuroblastoma-derived cells (SK-N-AS) were studied for their response to iron chelation, with a particular attention paid to iron-sensitive aconitase activity.We found that a direct consequence of chelating mitochondrial free iron in various cell systems is a concentration and time dependent loss of aconitase activity. Impairing aconitase activity was shown to precede decreased cell proliferation.We conclude that, if chelating excessive mitochondrial iron may be beneficial at some stage of the disease, great attention should be paid to not fully deplete mitochondrial iron store in order to avoid undesirable consequences.Friedreich ataxia (FRDA) is a severe neurological disease with progressive cerebellar ataxia associating cardiomyopathy. It originates from a triplet expansion in the first intron of the gene coding for frataxin and the resulting impaired transcription causes depletion of this mitochondrial protein [1]. The actual consensus states that frataxin function, through the handling of mitochondrial iron, is intimately related with the synthesis of iron-sulfur clusters (ISC) subsequently distributed to the various cell compartments [2]. A number of ISC containing enzymes play a crucial role in cell metabolism. In keeping with this, aconitase was found severely affected in Friedreich ataxia and its residual activity might be a crucial issue to determine the course of the disease [3]. Indeed, while the activity of the mitochondrial enzyme is determinant for the metabolic flux through the tricarboxylic acid in the mitochondria [4], the cytosolic counterpart of the aconitase is known to tightly regulate the overall iron metabolism of mammal cells [5]. Accordingly, loss of aconitase activity has been previously shown to trigger cell death of cardiac fibroblasts [6]. Beside the impaired ISC assembly, an increased susceptibility to oxidative insult [7] and a late mitochondrial iron
PGC-1α is Dispensable for Exercise-Induced Mitochondrial Biogenesis in Skeletal Muscle
Glenn C. Rowe, Riyad El-Khoury, Ian S. Patten, Pierre Rustin, Zolt Arany
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041817
Abstract: Exercise confers numerous health benefits, many of which are thought to stem from exercise-induced mitochondrial biogenesis (EIMB) in skeletal muscle. The transcriptional coactivator PGC-1α, a potent regulator of metabolism in numerous tissues, is widely believed to be required for EIMB. We show here that this is not the case. Mice engineered to lack PGC-1α specifically in skeletal muscle (Myo-PGC-1αKO mice) retained intact EIMB. The exercise capacity of these mice was comparable to littermate controls. Induction of metabolic genes after 2 weeks of in-cage voluntary wheel running was intact. Electron microscopy revealed no gross abnormalities in mitochondria, and the mitochondrial biogenic response to endurance exercise was as robust in Myo-PGC-1αKO mice as in wildtype mice. The induction of enzymatic activity of the electron transport chain by exercise was likewise unperturbed in Myo-PGC-1αKO mice. These data demonstrate that PGC-1α is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle, in sharp contrast to the prevalent assumption in the field.
The Variability of the Harlequin Mouse Phenotype Resembles that of Human Mitochondrial-Complex I-Deficiency Syndromes
Paule Bénit, Sergio Goncalves, Emmanuel Philippe Dassa, Jean-Jacques Brière, Pierre Rustin
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003208
Abstract: Background Despite the considerable progress made in understanding the molecular bases of mitochondrial diseases, no effective treatments have been developed to date. Faithful animal models would be extremely helpful for designing such treatments. We showed previously that the Harlequin mouse phenotype was due to a specific mitochondrial complex I deficiency resulting from the loss of the Apoptosis Inducing Factor (Aif) protein. Methodology/Principal Findings Here, we conducted a detailed evaluation of the Harlequin mouse phenotype, including the biochemical abnormalities in various tissues. We observed highly variable disease expression considering both severity and time course progression. In each tissue, abnormalities correlated with the residual amount of the respiratory chain complex I 20 kDa subunit, rather than with residual Aif protein. Antioxidant enzyme activities were normal except in skeletal muscle, where they were moderately elevated. Conclusions/Significance Thus, the Harlequin mouse phenotype appears to result from mitochondrial respiratory chain complex I deficiency. Its features resemble those of human complex I deficiency syndromes. The Harlequin mouse holds promise as a model for developing treatments for complex I deficiency syndromes.
Friedreich's ataxia: the vicious circle hypothesis revisited
Aurélien Bayot, Renata Santos, Jean-Michel Camadro, Pierre Rustin
BMC Medicine , 2011, DOI: 10.1186/1741-7015-9-112
Abstract: Friedreich's ataxia (FA), the most prevalent form of autosomal recessive cerebellar ataxia in Caucasians, is characterised by progressive ataxia and dysarthria [1]. The symptoms usually become apparent around puberty, although onset may occur much later in life (> 60 years old). The neurological features include sensory neuropathy, deep sensory impairment, signs of pyramidal tract involvement and progressive cerebellar dysfunction. The nonneurological manifestations vary, but among them hypertrophic cardiomyopathy is common. Diabetes mellitus occurs in approximately one-third of FA patients [1]. FA therefore appears to be a rather heterogeneous disorder. In the vast majority of cases, it is caused by a GAA trinucleotide repeat expansion in the first intron of the frataxin-encoding gene (FXN), which results in decreased gene expression and partial loss of function of the frataxin protein in the mitochondrial matrix [2]. Frataxin has been shown to interact with the iron-sulphur cluster (ISC) assembly machinery [3] (Figure 1). Frataxin loss of function therefore can result in ISC-containing protein (ISP) deficiency, decreasing aconitase and mitochondrial respiratory chain activity [4], but it also results in hypersensitivity to oxidative stress [5,6] and accumulation of iron in affected organs [7].Except perhaps for gene-targeting therapies, to develop rational treatments for FA, we need to better elucidate the actual mechanism underlying the disease pathophysiology. On the basis of recent studies of various conditions in many different organisms (from microorganisms to humans), including human diseases originating from mutations in genes functionally related to FXN, we tried to reconcile the various pathogenic manifestations resulting from frataxin depletion and argue for a prominent and early role of impaired responses to oxidative insults in FA.The cellular consequences of frataxin loss of function were initially described as faulty iron handling, impaired ISC synth
Impaired Nuclear Nrf2 Translocation Undermines the Oxidative Stress Response in Friedreich Ataxia
Vincent Paupe, Emmanuel P. Dassa, Sergio Goncalves, Fran?oise Auchère, Maria L?nn, Arne Holmgren, Pierre Rustin
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004253
Abstract: Background Friedreich ataxia originates from a decrease in mitochondrial frataxin, which causes the death of a subset of neurons. The biochemical hallmarks of the disease include low activity of the iron sulfur cluster-containing proteins (ISP) and impairment of antioxidant defense mechanisms that may play a major role in disease progression. Methodology/Principal Findings We thus investigated signaling pathways involved in antioxidant defense mechanisms. We showed that cultured fibroblasts from patients with Friedreich ataxia exhibited hypersensitivity to oxidative insults because of an impairment in the Nrf2 signaling pathway, which led to faulty induction of antioxidant enzymes. This impairment originated from previously reported actin remodeling by hydrogen peroxide. Conclusions/Significance Thus, the defective machinery for ISP synthesis by causing mitochondrial iron dysmetabolism increases hydrogen peroxide production that accounts for the increased susceptibility to oxidative stress.
Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice
Manuel Schiff, Paule Bénit, Riyad El-Khoury, Dimitri Schlemmer, Jean-Fran?ois Benoist, Pierre Rustin
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028823
Abstract: Background Therapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding efficacy are limited. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD. Methods and Findings Before launching long and expensive animal studies, we showed that palmitate afforded long-term death-protection in 3 CI-mutant human fibroblasts cell lines. We next demonstrated that using the Harlequin mouse, it was possible to draw solid conclusions on the efficacy of a 5-month-HFD on neurodegenerative symptoms. Moreover, we could identify a group of highly responsive animals, echoing the high variability of the disease progression in Harlequin mice. Conclusions These results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized. They also positively prefigure HFD-trials in OXPHOS-deficient patients.
Using artwork to understand the experience of mental illness: Mainstream artists and Outsider artists
Rustin, Terry A.
GMS Psycho-Social-Medicine , 2008,
Abstract: Objective: Artwork and psychiatric disorders are often linked. Accomplished artists with psychiatric disorders express themselves and their emotional distress through their works, and art therapists use the visual arts to help clients understand their problems and cope with them. There have been a number of psychiatric patients with no previous art training who produced artwork that many consider museum-worthy (Art Brut, or Outsider Art.) For the past two years, I have used artwork in another way: to better understand my clients and their psychiatric disorders.Methods: Presented here are paintings I have made about the mental illness experience of some of my clients, all well known to me through their therapy. It is a form of visual psychodrama, in which I reverse roles with the client through the paintings. My goal has been to experience the stresses felt by my clients so that I can understand them better.Results: The paintings have served as a point of embarkation for therapy sessions, as a means of clarifying a client’s experience, and as a way to show clients that their therapist is attending to what they say. Countertransference undoubtedly plays a role in my choice of clients and their portrayals, but the intent is to help me better understand the clients’ experiences.Included here are images of some of these paintings with a short psychiatric history of the client about whom they were made. Accompanying each one are responses from the clients upon viewing “their” paintings, and a discussion of the client’s psychiatric disorder.Conclusions: Making these paintings has helped me understand better the feelings of isolation, rejection, loss, and alienation that many of my clients experience every day. In turn, they tell me that viewing the paintings is an intense experience for them as well. As an outsider artist, I must leave it to the viewer to determine whether or not these paintings qualify as “art.”
Use of Human Cancer Cell Lines Mitochondria to Explore the Mechanisms of BH3 Peptides and ABT-737-Induced Mitochondrial Membrane Permeabilization
Nelly Buron,Mathieu Porceddu,Magali Brabant,Diana Desgué,Cindy Racoeur,Myriam Lassalle,Christine Péchoux,Pierre Rustin,Etienne Jacotot,Annie Borgne-Sanchez
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009924
Abstract: Current limitations of chemotherapy include toxicity on healthy tissues and multidrug resistance of malignant cells. A number of recent anti-cancer strategies aim at targeting the mitochondrial apoptotic machinery to induce tumor cell death. In this study, we set up protocols to purify functional mitochondria from various human cell lines to analyze the effect of peptidic and xenobiotic compounds described to harbour either Bcl-2 inhibition properties or toxic effects related to mitochondria. Mitochondrial inner and outer membrane permeabilization were systematically investigated in cancer cell mitochondria versus non-cancerous mitochondria. The truncated (t-) Bid protein, synthetic BH3 peptides from Bim and Bak, and the small molecule ABT-737 induced a tumor-specific and OMP-restricted mitochondrio-toxicity, while compounds like HA-14.1, YC-137, Chelerythrine, Gossypol, TW-37 or EM20-25 did not. We found that ABT-737 can induce the Bax-dependent release of apoptotic proteins (cytochrome c, Smac/Diablo and Omi/HtrA2 but not AIF) from various but not all cancer cell mitochondria. Furthermore, ABT-737 addition to isolated cancer cell mitochondria induced oligomerization of Bax and/or Bak monomers already inserted in the mitochondrial membrane. Finally immunoprecipatations indicated that ABT-737 induces Bax, Bak and Bim desequestration from Bcl-2 and Bcl-xL but not from Mcl-1L. This study investigates for the first time the mechanism of action of ABT-737 as a single agent on isolated cancer cell mitochondria. Hence, this method based on MOMP (mitochondrial outer membrane permeabilization) is an interesting screening tool, tailored for identifying Bcl-2 antagonists with selective toxicity profile against cancer cell mitochondria but devoid of toxicity against healthy mitochondria.
Mitochondrial activities in human cultured skin fibroblasts contaminated by Mycoplasma hyorhinis
Niklas Darin, Norman Kadhom, Jean-Jacques Brière, Dominique Chretien, Cécile M Bébéar, Agnès R?tig, Arnold Munnich, Pierre Rustin
BMC Biochemistry , 2003, DOI: 10.1186/1471-2091-4-15
Abstract: Here we report the lack of significant consequence of a heavy contamination by the frequently encountered mycoplasma strain, M. hyorhinis, on the determination of respiratory chain activities, but the potential interference when assaying citrate synthase. Contamination by M. hyorhinis was detected by fluorescent imaging and further quantified by the determination of the mycoplasma-specific phosphate acetyltransferase activity. Noticeably, this latter activity was not found equally distributed in various mycoplasma types, being exceptionally high in M. hyorhinis.While we observed a trend for respiration reduction in heavily contaminated cells, no significant and specific targeting of any respiratory chain components could be identified. This suggested a potential interference with cell metabolism rather than direct interaction with respiratory chain components.The mollicutes (lat., molis, soft; cutis, skin) or mycoplasmas, with over 100 different species, are the smallest self-replicating organisms known at present and constitute a distinct class within the prokaryotes characterized by their lack of a rigid cell wall. They can be classified into fermentative strains, which gain energy by fermentation of carbohydrates and non-fermentative strains that are unable to metabolize carbohydrates via glycolysis. The mycoplasmas are extra cellular parasites usually attached to the external surface of cells, but can also penetrate these [1]. In humans, M. pneumoniae is a frequent cause of respiratory infections, and is at the origin of approximately 20% of all community-acquired pneumonias [2]. The mycoplasmas may also lead to genitourinary and neonatal infections [3]. In addition, mycoplasmas have been implicated in the pathogenesis of AIDS [4] and rheumatoid arthritis [5], although their precise contribution is still under debate. Being 'minimal cells', mycoplasma have also been used to investigate the machinery of self-replicating organisms [6].Beside health problems, mycop
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