Publications (66) View all
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Article: Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders.
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ABSTRACT: Human prion diseases are a heterogeneous group of fatal neurodegenerative disorders, characterized by the deposition of the partially protease-resistant prion protein (PrP(res)), astrocytosis, neuronal loss and spongiform change in the brain. Among inherited forms that represent 15% of patients, different phenotypes have been described depending on the variations detected at different positions within the prion protein gene. Here, we report a new mechanism governing the phenotypic variability of inherited prion diseases. First, we observed that the substitution at residue 211 with either Gln or Asp leads to distinct disorders at the clinical, neuropathological and biochemical levels (Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker syndrome with abundant amyloid plaques and tau neurofibrillar pathology). Then, using molecular dynamics simulations and biophysical characterization of mutant proteins and an in vitro model of PrP conversion, we found evidence that each substitution impacts differently the stability of PrP and its propensity to produce different protease resistant fragments that may contribute to the phenotypical switch. Thus, subtle differences in the PrP primary structure and stability are sufficient to control amyloid plaques formation and tau abnormal phosphorylation and fibrillation. This mechanism is unique among neurodegenerative disorders and is consistent with the prion hypothesis that proposes a conformational change as the key pathological event in prion disorders.Human Molecular Genetics 09/2012; · 7.64 Impact Factor -
Article: Fatal rhabdomyolysis in 2 children with LPIN1 mutations.
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ABSTRACT: We report 2 cases of fatal rhabdomyolysis in children carrying an LPIN1 mutations preceded by similar electrocardiogram changes, including diffuse symmetrical high-amplitude T waves. Our report underlines the severity of this disease and the need for active management of episodes of rhabdomyolysis in a pediatric intensive care unit.The Journal of pediatrics 04/2012; 160(6):1052-4. · 4.02 Impact Factor -
Article: Hemojuvelin: a new link between obesity and iron homeostasis.
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ABSTRACT: The adipose tissue may play an active role in systemic iron regulation and this role may be determinant in obese patients. Indeed, we reported previously that hepcidin, the iron-regulatory hormone, is expressed in adipose tissue and its messenger RNA (mRNA) expression is increased in adipose tissue of morbidly obese patients. The objectives of this study were to characterize the status of hemojuvelin (HJV), another iron-regulatory protein, within the adipose tissue of morbidly obese patients. Since cell-associated HJV acts as a coreceptor of bone morphogenetic protein (BMP) to enhance hepcidin expression in liver cells, we investigated the possible involvement of this pathway in adipose tissue in regulating hepcidin expression. HJV expression was studied in adipose tissue of morbidly obese patients. Soluble HJV blood concentrations were assessed. Hepcidin regulation through BMP pathway was investigated in cultured adipocytes. HJV was expressed both at mRNA and protein levels in adipose tissue. Moreover, its mRNA expression was highly increased in adipose tissue of obese patients and correlated with mRNA hepcidin expression levels. Interestingly, HJV expressed by adipose tissue may be effective since cultured adipocytes increased their hepcidin expression when challenged with BMP2 through Smad effectors. In addition, blood concentrations of soluble HJV were significantly increased. In conclusion, adipose tissue may influence iron homeostasis in obese patients by expressing major iron-regulatory proteins and the BMP signaling pathway could be involved in regulating hepcidin expression in this tissue.Obesity 02/2011; 19(8):1545-51. · 4.28 Impact Factor -
Article: Filamin-A and Myosin VI colocalize with fibrillary Tau protein in Alzheimer's disease and FTDP-17 brains.
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ABSTRACT: Tauopathies, including Alzheimer's disease (AD), fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease and progressive supranuclear palsy, are neurodegenerative disorders neuropathologically characterized by the presence of intraneuronal fibrillary inclusions composed of abnormally phosphorylated-Tau. Tau protein is a neuronal microtubule-associated protein (MAP) involved in microtubules polymerization and stabilization. So far, the molecular mechanisms underlying Tau-mediated cellular toxicity remain elusive. To address the determinants of Tau neurotoxicity, we previously performed a misexpression screening in a Drosophila tauopathy model to identify genetic modifiers of the human Tau-induced neurodegeneration. We identified several components of the actin network as modifiers of Tau V337M-induced neurodegeneration, i.e. Filamin-A, Myosin VI, Paxillin and Transgelin-3. The aim of this study was to assess whether these genetic interactions were associated with a colocalization of the proteins (i) in the brains of patients with Tau pathologies, and (ii) in the brain of transgenic mice overexpressing human mutant Tau. We found that Filamin-A and Myosin VI indeed colocalize with fibrillary Tau protein in AD and FTDP-17 and in Thy-Tau22 transgenic mice.Brain research 05/2010; 1345:182-9. · 2.46 Impact Factor -
Article: Neuropathology of holoprosencephaly.
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ABSTRACT: Holoprosencephaly (HPE) is a brain malformation which results from a primary defect in induction and patterning of the rostral neural tube during early embryogenesis and usually considered as an impaired cleavage of the prosencephalon. The review of neuropathologic findings highlights a complex malformation involving not only the prosencephalon but also the whole brain, the eyes, and the cerebral vascularization. The classical form of HPE is divided in three sub-types according to DeMyer classification, although the spectrum is far wider, ranging from the most severe, aprosencephaly/atelencephaly, to milder forms such as syntelencephaly and to the less severe ends of the spectrum. Macroscopy and microscopy abnormality patterns are described extensively, allowing a comparison of the anatomic features between each form. Disturbances observed in the main cerebral structures including the basal ganglia, the commissures, the hippocampus, the brainstem, the cerebellum, and spinal cord are reviewed. Macroscopic and microscopic features of the ophthalmic anomalies are described, as well as brain vascular and associated central nervous system malformations.American Journal of Medical Genetics Part C Seminars in Medical Genetics 02/2010; 154C(1):109-19. · 4.06 Impact Factor
