Papers by Stéphane Fourcade
Human Molecular Genetics, Apr 20, 2013
Biochimie, Mar 1, 2014
X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating dise... more X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating disease (minimal incidence 1:17,000). It is often lethal and currently lacks a satisfactory therapy. The disease is caused by loss of function of the ABCD1 gene, a peroxisomal ATP-binding cassette transporter, resulting in the accumulation of VLCFA (very long-chain fatty acids) in organs and plasma. Understanding of the aetiopathogenesis is a prerequisite for the development of novel therapeutic strategies. Functional genomics analysis of an ABCD1 null mouse, a mouse model for adrenomyeloneuropathy, has revealed presymptomatic alterations in several metabolic pathways converging on redox and bioenergetic homeostasis, with failure of mitochondrial OXPHOS disruption and mitochondrial depletion. These defects could be major contributors to the neurodegenerative cascade, as has been reported in several neurodegenerative disorders. Drugs targeting the redox imbalance/mitochondria dysfunction interplay have shown efficacy at halting axonal degeneration and associated disability in the mouse, and thus offer therapeutic hope.
Cell reports, Jan 8, 2018
Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently un... more Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with ...
Cell Reports, May 1, 2018
Highlights d Gsk3b kinase activity and inflammation are increased in mice models of Rett syndrome... more Highlights d Gsk3b kinase activity and inflammation are increased in mice models of Rett syndrome d Specific inhibition of Gsk3b reduces motor deficits and improves general well-being d Neuronal morphology is restored in vitro and in vivo and excitatory synapses altered d Gsk3b is a potential therapeutic target in Rett syndrome treatment
Journal of Clinical Investigation
Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome pr... more Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator
Objective: Axonal degeneration is a main contributor to disability in progressive neurodegenerati... more Objective: Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X-adrenoleukodystrophy (X-ALD). Methods: X-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X-ALD. Results: Here, we prove the capability of the antioxidants N-acetyl-cysteine, a-lipoic acid, and a-tocopherol to scavenge ...
Abstracts of the 47th Annual Meeting of the SENP (Société Européenne De Neurologie Pédiatrique), 2019
Clinical Genetics
CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a pub... more CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on Rare Diseases currently consists of 75 research groups belonging to universities, research centers and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical and cellular research of rare diseases. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this paper, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions towards the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to rare disease research. This article is protected by copyright. All rights reserved.
Cell death and differentiation, Jan 27, 2015
Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration proce... more Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired.Cell Death and Differentiation advance online publication, 27 March 2015; doi:10.1038/cdd.2015.20.
Human Molecular Genetics, 2013
<b>Copyright information:</b>Taken from "PeroxisomeDB: a database for the peroxi... more <b>Copyright information:</b>Taken from "PeroxisomeDB: a database for the peroxisomal proteome, functional genomics and disease"Nucleic Acids Research 2006;35(Database issue):D815-D822.Published online 28 Nov 2006PMCID:PMC1747181.© 2006 The Author(s) Tool for the prediction of the three peroxisomal target signals: PTS1, PTS2 and PEX19BS. Motifs within the query sequence are identified using 'Do-It-YourSelf Block Search' in BLOCKS server.
Advances in Experimental Medicine and Biology, 2003
X-linked adrenoleukodystrophy (X-ALD) is a recessive neurologic disease with an incidence among m... more X-linked adrenoleukodystrophy (X-ALD) is a recessive neurologic disease with an incidence among males of 1/17 000. Since the identification of the X-ALD gene (ABCD1) ten years ago (Mosser et al 1993), no satisfactory therapy has been available. A close homologue (ABCD2) was then cloned and presented as a putative modifier gene that could account for some of the extreme phenotypic variability of X-ALD (Lombard-Platet et al 1996). The inducibility of Abcd2 by the hypolipidemic drug fenofibrate in the liver of rodents (Albet et al 1997), correlated to a partial normalisation of the biochemical phenotype of X-ALD (Netik et al 1999), opened up the way of a pharmacological therapy of X-ALD. The basis of such a therapy and the results obtained chiefly in rodents will be presented in this chapter.
Neurology, 2022
Background and Objectives:Genetic white matter disorders (GWMD) are of heterogeneous origin, with... more Background and Objectives:Genetic white matter disorders (GWMD) are of heterogeneous origin, with more than a hundred causal genes identified to date. Classical targeted approaches achieve a molecular diagnosis in only half of all patients. Here we aim to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD patients, while identifying novel phenotypes and candidate genes.Methods:A case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm, based on the network expansion of a seed group of GWMD-related genes, derived from the HPO t...
<b>Copyright information:</b>Taken from "PeroxisomeDB: a database for the peroxi... more <b>Copyright information:</b>Taken from "PeroxisomeDB: a database for the peroxisomal proteome, functional genomics and disease"Nucleic Acids Research 2006;35(Database issue):D815-D822.Published online 28 Nov 2006PMCID:PMC1747181.© 2006 The Author(s)
© The Author(s) 2014. This article is published with open access at Springerlink.com proteasome f... more © The Author(s) 2014. This article is published with open access at Springerlink.com proteasome function and redox as well as metabolic home-ostasis. These findings provide the first evidence that links impaired autophagy to X-ALD, which may yield a therapy based on autophagy activators for adrenomyeloneuropathy patients.
Neurology, 2019
Objective: Axonal degeneration is a main contributor to disability in progressive neurodegenerati... more Objective: Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases such as multiple sclerosis or adrenoleukodystrophy (X-ALD), in which redox homeostasis, bioenergetic failure and/or inflammation are often identified as pathogenic factors. Background: X-ALD is a monogenic neurometabolic disorder caused by inactivation of the peroxisomal transporter of very long-chain fatty acids ABCD1. In mice, ABCD1 loss causes late onset, progressive axonal degeneration in the spinal cord’s corticospinal tracts in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Design/Methods: Here we are using models of X-ALD to: i) investigate if high oral doses of biotin (MD1003) are able to improve the clinical signs of the disease (axonal degeneration and locomotor deficits), and ii) elucidate by which molecular and biochemical mechanisms it operates. Results: Our results indicate that treatment with MD100...
L'adrenoleucodystrophie lie a l'X (X-ALD) est une maladie genetique peroxysomiale caracte... more L'adrenoleucodystrophie lie a l'X (X-ALD) est une maladie genetique peroxysomiale caracterisee par une demyelinisation du systeme nerveux central. Elle est associee a un defaut biochimique de la b-oxydation des acides gras a tres longue chaine (AGTLC) qui conduit a leur accumulation plasmatique et tissulaire. Le gene ABCD1, dont la mutation est responsable de la maladie, est un membre de la famille des transporteurs ABC (" ATP binding cassette ") suppose etre associe a l'entree des AGTLC dans le peroxysome. Le gene ABCD2, le plus proche homologue du gene ABCD1, code un hemitransporteur ABC qui pourrait remplir une fonction apparentee et ainsi pallier la deficience du gene ABCD1. En effet, sa surexpression dans des fibroblastes de patients X-ALD entraine une normalisation du taux d'AGTLC. Une induction du gene par des traitements pharmacologiques pourrait donc devenir une piste therapeutique interessante pour lutter contre la maladie a condition de surmonter...
Trabajo presentado en la V Spanish Worm Meeting, celebrada en Salamanca el 5 y 6 de marzo de 2015.
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Papers by Stéphane Fourcade