Bertrand Friguet

Pierre and Marie Curie University - Paris 6, Lutetia Parisorum, Île-de-France, France

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Publications (146)585.06 Total impact

  • Eduardo Silva, Felipe Avila, Bertrand Friguet
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    ABSTRACT: This chapter describes the photosensitizing properties of the colored compounds generated in the human lens during aging and their effect on the proteasomal system. All the experiments were performed using UVA-visible light and a low oxygen concentration, which corresponds to the actual condition in this tissue. The colored and cross-linked lens proteins, which are increasingly generated as a function of aging, do not undergo additional cross-linking when exposed to UVA-visible light under a low oxygen pressure. The photosensitized damage observed in these conditions is restricted to oxidation processes located near the chromophore. Interestingly, a glucose-derived chromophore with identical spectral and chromatographic properties as those found in one of the components of the water-soluble fractions of cataractous human eye lenses produces increased protein oxidation and protein cross-linking when lens proteins were exposed to UVA-visible light under a 5% oxygen atmosphere. In addition, increased proteasome peptidase activity was observed. The behavior of this protective system in human lenses corresponding to various age groups is also described in this chapter.
    Studies on the Cornea and Lens, Series: Oxidative Stress in Applied Basic Research and Clinical Practice edited by Babizhayev, M.A., Li, D.W.-C, Kasus-Jacobi, A, Žorić, L, Alió, 12/2015: chapter Chapter 14: pages 239-274; Springer., ISBN: ISBN 978-1-4939-1934-5
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    ABSTRACT: The cellular basis of age-related tissue deterioration remains largely obscure. The ability to activate compensatory mechanisms in response to environmental stress is an important factor for survival and maintenance of cellular functions. Autophagy is activated both under short and prolonged stress and is required to clear the cell of dysfunctional organelles and altered proteins. We report that specific autophagy inhibition in muscle has a major impact on neuromuscular synaptic function and, consequently, on muscle strength, ultimately affecting the lifespan of animals. Inhibition of autophagy also exacerbates aging phenotypes in muscle, such as mitochondrial dysfunction, oxidative stress, and profound weakness. Mitochondrial dysfunction and oxidative stress directly affect acto-myosin interaction and force generation but show a limited effect on stability of neuromuscular synapses. These results demonstrate that age-related deterioration of synaptic structure and function is exacerbated by defective autophagy.
    Cell reports. 08/2014;
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    ABSTRACT: Skin aging is the result of intrinsic chronological aging and photoaging, due to UV exposure, that both share important histological modifications and molecular features, including alterations of proteins. One of the main damage is glycation that occurs when reducing sugars react non-enzymatically with proteins. This reaction also happens when the dicarbonyl compounds GO (glyoxal) and MG (methylglyoxal), which are glucose derivatives, react with proteins. These compounds can be detoxified by the glyoxalase system composed of two enzymes, Glo1 (glyoxalase I) and Glo2 (glyoxalase II). The aims of the present mini-review are to briefly summarize our current knowledge of the biological roles of these enzymes in aging and then discuss the relevance of studying the role of glycation and of detoxifying systems in human skin aging.
    Biochemical Society Transactions 04/2014; 42(2):518-22. · 2.59 Impact Factor
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    ABSTRACT: Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau.
    Experimental Neurology 01/2014; · 4.65 Impact Factor
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    ABSTRACT: ATP-dependent proteases are currently emerging as key regulators of mitochondrial functions. Among these proteolytic systems, Lon protease is involved in the control of selective protein turnover in the mitochondrial matrix. In the absence of Lon, yeast cells have been shown to accumulate electron-dense inclusion bodies in the matrix space, to loose integrity of mitochondrial genome and to be respiratory deficient. In order to address the role of Lon in mitochondrial functionality in human cells, we have set up a HeLa cell line stably transfected with a vector expressing a shRNA under the control of a promoter which is inducible with doxycycline. We have demonstrated that reduction of Lon protease results in a mild phenotype in this cell line in contrast with what have been observed in other cell types such as WI-38 fibroblasts. Nevertheless, deficiency in Lon protease led to an increase in ROS production and to an accumulation of carbonylated protein in the mitochondria. Our study suggests that Lon protease has a wide variety of targets and is likely to play different roles depending of the cell type.
    Biochimie 12/2013; · 3.14 Impact Factor
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    ABSTRACT: MicroRNAs are a novel class of powerful endogenous regulators of gene expression. MiR-378 and miR-378* are localized in the first intron of the Ppargc1b gene that codes the transcriptional co-activator PGC-1β. The latter regulates energy expenditure as well as mitochondrial biogenesis. The miR-378:miR-378* hairpin is highly expressed in cardiac cells. To better assess their role in cardiomyocytes, we identified miR-378 and miR-378* targets via a proteomic screen. We established H9c2 cellular models of overexpression of miR-378 and miR-378* and identified a total of 87 down regulated proteins in the presence of either one of these miRs. Functional annotation clustering showed that miR-378 and miR-378* regulate related pathways in cardiomyocytes, including energy metabolism, notably glycolysis, cytoskeleton, notably actin filaments and muscle contraction. Using bioinformatics algorithms we found that 20 proteins were predicted as direct targets of the miRs. We validated 8 of these targets by quantitative RT-PCR and luciferase reporter assay. We found that miR-378 targets Lactate Dehydrogenase A and impacts on cell proliferation and survival whereas miR-378* targets cytoskeleton proteins actin and vimentin. Proteins involved in endoplasmic reticulum stress response such as chaperone and/or calcium buffering proteins GRP78, PPIA (Cyclophilin A), calumenin and GMMPA involved in glycosylation are repressed by these miRs. Our results show that the miR-378/378* hairpin establishes a connection between energy metabolism, cytoskeleton remodeling and endoplasmic reticulum function through post-transcriptional regulation of key proteins involved in theses pathways.
    Molecular &amp Cellular Proteomics 09/2013; · 7.25 Impact Factor
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    ABSTRACT: Methionine Sulfoxide Reductases (Msrs) are key enzymes proficient in catalyzing the reduction of oxidized methionines. This reductive trait is essential to maintain cellular redox homeostasis from bacteria to mammals and is also regarded as a potential mechanism to regulate protein activities and signaling pathways, considering the inactivating effects that can be induced by methionine oxidation. In this study, we have generated stable human embryonic kidney HEK293 clones with an altered Msr system by silencing the expression of the main Msr elements - either MsrA, MsrB1 or MsrB2. The isolated clones - the single mutants MsrA, MsrB1, MsrB2 and double mutant MsrA/B1 - show a reduced Msr activity and an exacerbated sensitivity towards oxidative stress. A 2 Dimensional Difference In-Gel Electrophoresis (DIGE) analysis was performed on the Msr-silenced cells grown under basal conditions or submitted to oxidative stress. This proteomic analysis revealed that the disruption of the Msr system mainly affects proteins with redox, cytoskeletal or protein synthesis and maintenance roles. Interestingly, most of the proteins found altered in the different Msr mutants were also identified as potential Msr substrates and have been associated with redox or aging processes in previous studies. This study, through an extensive analysis of Msr-inhibited mutants, offers a valuable input on the cellular network of a crucial maintenance system such as Methionine Sulfoxide Reductases.
    Free Radical Biology and Medicine 08/2013; · 5.27 Impact Factor
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    ABSTRACT: Aging is accompanied by the gradual deterioration of cell functions. Particularly, mitochondrial dysfunction, associated with an accumulation of damaged proteins, is of key importance due to the central role of these organelles in cellular metabolism. However, the detailed molecular mechanisms involved in such impairment have not been completely elucidated. In the present study, proteomic analyses looking at both changes at the expression level as well as to glycative modifications of the mitochondrial proteome were performed. Two-dimensional difference gel electrophoresis analysis revealed 16 differentially expressed proteins with aging. Thirteen exhibited a decreased expression and are crucial enzymes related to OXPHOS chain complex I/V components, TCA cycle or fatty acid β-oxidation reaction. On the other hand, 2 enzymes involved in fatty acid β-oxidation cycle were increased in aged mitochondria. Immunodetection and further identification of glycated proteins disclosed a set of advanced glycation endproduct-modified proteins, including 6 enzymes involved in the fatty acid β-oxidation process, and 2 enzymes of the TCA/urea cycles. A crucial antioxidant enzyme, catalase, was among the most strongly glycated proteins. In addition, several AGE-damaged enzymes (aldehyde dehydrogenase 2, medium chain acyl-CoA dehydrogenase and 3-ketoacyl-CoA dehydrogenase) exhibited a decreased activity with age. Taken together, these data suggest that liver mitochondria in old rats suffer from a decline in their capacity for energy production, due to (i) decreased expression of OXPHOS complex I/V components and (ii) glycative damage to key fatty acid β-oxidation and TCA/urea cycle enzymes.
    Biochimica et Biophysica Acta 07/2013; · 4.66 Impact Factor
  • Experimental Gerontology 07/2013; 48(7):688–689. · 3.91 Impact Factor
  • Experimental Gerontology. 07/2013; 48(7):687–688.
  • Martin A Baraibar, Romain Ladouce, Bertrand Friguet
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    ABSTRACT: Increased protein carbonyl content is a hallmark of cellular and organismal aging. Protein damage leading to the formation of carbonyl groups derives from direct oxidation of several amino acids side chains but can also derive through protein adducts formation with lipid peroxidation products and dicarbonyl glycating compounds. All these modifications have been implicated during oxidative stress, aging and age-related diseases. However, in most cases, the proteins targeted by these deleterious modifications as well as their consequences have not yet been clearly identified. Indeed, this is essential to determine whether and how these modified proteins are impacting on cellular function, on the development of the senescent phenotype and the pathogenesis of age-related diseases. In this context, protein modifications occurring during aging and upon oxidative stress as well as main proteomic methods for detecting, quantifying and identifying oxidized proteins are described. Relevant proteomics studies aimed at monitoring the extent of protein carbonylation and identifying the targeted proteins in the context of aging and oxidative stress are also presented. Proteomics approaches, i.e. fluorescent based 2D-gel electrophoresis and mass spectrometry methods, represent powerful tools for monitoring at the proteome level the extent of protein oxidative and related modifications and for identifying the targeted proteins. BIOLOGICAL SIGNIFICANCE: Accumulation of damaged macromolecules, including oxidatively damaged (carbonylated) proteins, is a hallmark of cellular and organismal aging. Since protein carbonyls are the most commonly used marker of protein oxidation, different methods have been developed for the detection and quantification of carbonylated proteins. The identification of these protein targets is of valuable interest in order to understand the mechanisms by which damaged proteins accumulate and potentially affect cellular functions during oxidative stress, cellular senescence and/or aging in vivo. The specificity of hydrazide derivatives to carbonyl groups and the presence of a wide range of functional groups coupled to the hydrazide, allowed the design of novel strategies for the detection and quantification of carbonylated proteins. Of note is the importance of fluorescent probes for monitoring carbonylated proteins. Proteomics approaches, i.e. fluorescent based 2D-gel electrophoresis and mass spectrometry methods, represent powerful tools for monitoring at the proteome level the extent of protein oxidative and related modifications and for identifying the targeted proteins. This article is part of a Special Issue entitled: Protein Modifications.
    Journal of proteomics 05/2013; · 5.07 Impact Factor
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    ABSTRACT: Skeletal muscle ageing is characterized by a progressive and dramatic loss of muscle mass and strength leading to decreased muscular function resulting in muscle weakness which is often referred to as sarcopenia. Following the standardisation of "omics" approaches to study the genome (genomics) and the transcriptome (transcriptomics), the study of the proteins encoded by the genome, referred to as proteomics, is a tremendous challenge. Unlike the genome, the proteome varies in response to many physiological or pathological factors. In addition, the proteome is orders of magnitude more complex than the transcriptome due to post-translational modifications, protein oxidation and limited protein degradation. Proteomic studies, including the analysis of protein abundance as well as post-translational modified proteins have been shown to provide valuable information to unravel the key molecular pathways implicated in complex biological processes, such as tissue and organ ageing. In this article, we will describe proteomic approaches for the analysis of protein abundance as well as the specific protein targets for oxidative damage upon oxidative stress and/or during skeletal muscle ageing.
    Biogerontology 04/2013; · 3.19 Impact Factor
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    ABSTRACT: The Saccharomyces cerevisiae homolog of the ATP-dependent Lon protease, Pim1p, is essential for mitochondrial protein quality control, mitochondrial DNA maintenance and respiration. Here, we demonstrate that Pim1p activity declines in aging cells and that Pim1p deficiency shortens the replicative life span of yeast mother cells. This accelerated aging of pim1Δ cells is accompanied by elevated cytosolic levels of oxidized and aggregated proteins, as well as reduced proteasome activity. Overproduction of Hsp104p greatly diminishes aggregation of oxidized cytosolic proteins, rescues proteasome activity and restores life span of pim1Δ cells to near wild type levels. Our results show that defects in mitochondrial protein quality control have global intracellular effects leading to the increased generation of misfolded proteins and cytosolic protein aggregates, which are linked to a decline in replicative potential.
    Free Radical Biology and Medicine 12/2012; · 5.27 Impact Factor
  • Martin A Baraibar, Bertrand Friguet
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    ABSTRACT: Oxidatively modified proteins build-up with age results, at least in part, from the increase of reactive oxygen species and other toxic compounds originating from both cellular metabolism and external factors. Experimental evidence has also indicated that failure of protein maintenance is a major contributor to the age-associated accumulation of damaged proteins. We have previously shown that oxidized proteins as well as proteins modified by lipid peroxidation and glycoxidation adducts are accumulating in senescent human WI-38 fibroblasts and reported that proteins targeted by these modifications are mainly involved in protein maintenance, energy metabolism and cytoskeleton. Alterations in the proteome of human muscle adult stem cells upon oxidative stress have also been recently analyzed. The carbonylated proteins identified were also found to be involved in key cellular functions, such as carbohydrate metabolism, protein maintenance, cellular motility and protein homeostasis. More recently, we have built a database of proteins modified by carbonylation, glycation and lipid peroxidation products during aging and age-related diseases, such as neurodegenerative diseases. Common pathways evidenced by enzymes involved in intermediate metabolism were found targeted by these modifications, although different tissues have been examined. These results underscore the implication of potential deleterious effects of protein irreversible oxidative modifications in key cellular pathways during aging and in the pathogenesis of age-related diseases.
    Experimental gerontology 11/2012; · 3.34 Impact Factor
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    ABSTRACT: Proteins are continuously affected by various intrinsic and extrinsic factors. Damaged proteins influence several intracellular pathways and result in different disorders and diseases. Aggregation of damaged proteins depends on the balance between their generation and their reversal or elimination by protein repair systems and degradation, respectively. With regard to protein repair, only few repair mechanisms have been evidenced including the reduction of methionine sulfoxide residues by the methionine sulfoxide reductases, the conversion of isoaspartyl residues to L-aspartate by L-isoaspartate methyl transferase and deglycation by phosphorylation of protein-bound fructosamine by fructosamine-3-kinase. Protein degradation is orchestrated by two major proteolytic systems, namely the lysosome and the proteasome. Alteration of the function for both systems has been involved in all aspects of cellular metabolic networks linked to either normal or pathological processes. Given the importance of protein repair and degradation, great effort has recently been made regarding the modulation of these systems in various physiological conditions such as aging, as well as in diseases. Genetic modulation has produced promising results in the area of protein repair enzymes but there are not yet any identified potent inhibitors, and, to our knowledge, only one activating compound has been reported so far. In contrast, different drugs as well as natural compounds that interfere with proteolysis have been identified and/or developed resulting in homeostatic maintenance and/or the delay of disease progression.
    Molecular Aspects of Medicine 10/2012; · 10.38 Impact Factor
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    ABSTRACT: The presence of senile plaques in the brain is one of the pathological hallmarks of Alzheimer's disease (AD). The biogenesis and clearance of the amyloid β peptide (Aβ), the main component of the lesions, lie at the center of the pathogenesis of AD. In sporadic AD, the increase of Aβ levels seems to be indicative of failure of clearance mechanisms. We previously showed that the clearance of the wild type Aβ40 peptide by various neuronal and non-neuronal cells occurs through a same proteolytic process and that Ab degradation was primarily dictated by its conformational state (Panchal et al., 2007). To gain further insights on the role of the peptide conformation in the clearance mechanism of Ab, two Aβ40 peptides, known to be associated with amyloid angiopathy (Dutch and Flemish mutations), and the rodent Aβ40 peptide were catabolized by several cells by using the same experimental approach. The peptide fragments, generated by proteolytic cleavage of substrates in cell supernatants, were identified by LC-MS and the cleavage sites of proteases were deduced. In parallel, conformational states of wild type Aβ40 peptide and of the three Aβ40 variants were characterized by circular dichroism spectroscopy. We provide data suggesting that discrete conformational changes of Aβ40 peptide regulate its clearance rate by neuronal and non-neuronal cells.
    Protein and Peptide Letters 10/2012; · 1.99 Impact Factor
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    ABSTRACT: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of mice is a standard model of Parkinson's disease (PD). However, it does not reproduce functionally PD. Given the occurrence of PD during aging, symptoms might only be detected in MPTP-intoxicated mice after aging. To address this, mice injected with MPTP at 2.5 months were followed up to a maximum age of 21 months. There was no loss of dopamine cells with aging in control mice; moreover, the initial post-MPTP intoxication decrease in dopamine cell was no longer significant at 21 months. With aging, striatal dopamine level remained constant, but concentrations of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were markedly reduced in both groups. There was also a late impairment of fine motor skills. After MPTP intoxication, hyperactivity was immediately detected and it became greater than in control mice from 14 months of age; fine motor skills were also more impaired; both these symptoms were correlated with striatal dopamine, DOPAC and HVA concentrations. In bothgroups, neither motor symptoms nor dopamine changes worsened with age. These findings do not support the notion that PD develops with age in mice after MPTP intoxication and that the motor deficits seen are because of an aging process.
    Journal of Neurochemistry 06/2012; 122(5):1032-46. · 3.97 Impact Factor
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    ABSTRACT: Aging is characterized by progressive decline of major cell functions, associated with accumulation of altered macromolecules, particularly proteins. This deterioration parallels age-related dysfunction of mitochondria, thought to be a major determinant of this decline in cell function, since these organelles are both the main sources of reactive oxygen species and targets for their damaging effects. To investigate the link between glycation damages that accumulate with aging and the status of mitochondrial antioxidant enzymes, we identified, by mass spectrometry after two dimensional-gel electrophoresis and western blotting, advanced glycation end product-modified matrix proteins in rat liver mitochondria. Catalase appeared to be the only antioxidant enzyme markedly glycated in old rats. Immunogold labeling performed on isolated mitochondria confirmed the mitochondrial matrix location of this enzyme. The content of catalase protein in mitochondrial extract increased with aging whereas the catalase activity was not significantly modified, in spite of a significant increase rate of glycation. Treatment of catalase with the glycating agent fructose led to significant time-dependent inactivation of the enzyme, while methylglyoxal had no noticeable effect. Catalase was co-identified with unglycated glutathione peroxidase-1 in the mitochondrial extracts. Taken together, these results indicate that both anti-oxidant enzymes catalase and glutathione peroxidase-1 housed in liver mitochondria, exhibited a differential sensitivity to glycation; moreover, they lend support to the hypothesis that glycation damages targeting catalase with aging may severely affect its activity, suggesting a link between glycation stress and the age-related decline in antioxidant defense in the mitochondria.
    Biochimica et Biophysica Acta 06/2012; 1822(10):1527-34. · 4.66 Impact Factor
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    ABSTRACT: The ongoing revolution in aging research was manifested by the Second International Conference "Genetics of Aging and Longevity" (Moscow, April 22-25, 2012). The Conference goal was to identify the most promising areas of genetics, life expectancy, and aging, including: the search for longevity genes; the search for pharmacological agents that slow aging; the identification of biological age markers; and the identification of mechanisms by which the environment influences the aging rate.
    Aging 05/2012; 4(5):305-17. · 4.70 Impact Factor
  • Martin A Baraibar, Bertrand Friguet
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    ABSTRACT: Accumulation of oxidized and damaged proteins is a hallmark of the aging process in different organs and tissues. Intracellular protein degradation is normally the most efficient mechanism to prevent toxicity associated with the accumulation of altered proteins without affecting the cellular reserves of amino acids. Protein degradation by the proteasomal system is a key process for the maintenance of cellular protein homeostasis and has come into the focus of aging research during the last decade. During the last few years, several lines of evidence have indicated that proteasome function is impaired during aging, suggesting that this decreased activity might be causally related to the aging process and the occurrence of age-associated diseases. This chapter reviews the proteasome status in organs, tissues, cells, and model organisms during aging as well as the molecular mechanisms involved in the age-related decline of proteasome function. Finally, interventions aimed at rejuvenating proteasome function as a potential antiaging strategy are discussed.
    Progress in molecular biology and translational science 01/2012; 109:249-75. · 2.32 Impact Factor

Publication Stats

5k Citations
585.06 Total Impact Points


  • 2008–2014
    • Pierre and Marie Curie University - Paris 6
      • Institut de myologie
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • University of Gothenburg
      • Institutionen för cell- molekylärbiologi
      Göteborg, Vaestra Goetaland, Sweden
  • 1999–2012
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
  • 2010–2011
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
  • 2004–2011
    • Pontifical Catholic University of Chile
      • • Facultad de Ciencias Biológicas
      • • Departamento de Química Física
      Santiago, Region Metropolitana de Santiago, Chile
  • 2003
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
  • 2002
    • Université de Vincennes - Paris 8
      Saint-Denis, Île-de-France, France
  • 1996–2002
    • Case Western Reserve University
      • Department of Physiology and Biophysics
      Cleveland, OH, United States
  • 1989–1996
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France
  • 1995
    • Bar Ilan University
      Gan, Tel Aviv, Israel
  • 1994
    • National Heart, Lung, and Blood Institute
      • Biochemistry and Biophysics Center
      Maryland, United States
    • National Institutes of Health
      • Chemical Biology Laboratory
      Bethesda, MD, United States
  • 1990
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1986–1989
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire
      Strasburg, Alsace, France