Showing papers by "Jean-Louis Mandel published in 2009"

T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase

Abstract: Skeletal muscle contraction is triggered by the excitation-contraction (E-C) coupling machinery residing at the triad, a membrane structure formed by the juxtaposition of T-tubules and sarcoplasmic reticulum (SR) cisternae. The formation and maintenance of this structure is key for muscle function but is not well characterized. We have investigated the mechanisms leading to X-linked myotubular myopathy (XLMTM), a severe congenital disorder due to loss of function mutations in the MTM1 gene, encoding myotubularin, a phosphoinositide phosphatase thought to have a role in plasma membrane homeostasis and endocytosis. Using a mouse model of the disease, we report that Mtm1-deficient muscle fibers have a decreased number of triads and abnormal longitudinally oriented T-tubules. In addition, SR Ca(2+) release elicited by voltage-clamp depolarizations is strongly depressed in myotubularin-deficient muscle fibers, with myoplasmic Ca(2+) removal and SR Ca(2+) content essentially unaffected. At the molecular level, Mtm1-deficient myofibers exhibit a 3-fold reduction in type 1 ryanodine receptor (RyR1) protein level. These data reveal a critical role of myotubularin in the proper organization and function of the E-C coupling machinery and strongly suggest that defective RyR1-mediated SR Ca(2+) release is responsible for the failure of muscle function in myotubular myopathy.

Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation

Abstract: Bardet-Biedl syndrome (BBS) is an inherited ciliopathy generally associated with severe obesity, but the underlying mechanism remains hypothetical and is generally proposed to be of neuroendocrine origin. In this study, we show that while the proliferating preadipocytes or mature adipocytes are nonciliated in culture, a typical primary cilium is present in differentiating preadipocytes. This transient cilium carries receptors for Wnt and Hedgehog pathways, linking this organelle to previously described regulatory pathways of adipogenesis. We also show that the BBS10 and BBS12 proteins are located within the basal body of this primary cilium and inhibition of their expression impairs ciliogenesis, activates the glycogen synthase kinase 3 pathway, and induces peroxisome proliferator-activated receptor nuclear accumulation, hence favoring adipogenesis. Moreover, adipocytes derived from BBS-patients' dermal fibroblasts in culture exhibit higher propensity for fat accumulation when compared to controls. This strongly suggests that a peripheral primary dysfunction of adipogenesis participates to the pathogenesis of obesity in BBS.

Cells Lacking the Fragile X Mental Retardation Protein (FMRP) have Normal RISC Activity but Exhibit Altered Stress Granule Assembly

Abstract: The fragile X mental retardation protein (FMRP) is an RNA-binding protein involved in the mRNA metabolism. The absence of FMRP in neurons leads to alterations of the synaptic plasticity, probably as a result of translation regulation defects. The exact molecular mechanisms by which FMRP plays a role in translation regulation have remained elusive. The finding of an interaction between FMRP and the RNA interference silencing complex (RISC), a master of translation regulation, has suggested that both regulators could be functionally linked. We investigated here this link, and we show that FMRP exhibits little overlap both physically and functionally with the RISC machinery, excluding a direct impact of FMRP on RISC function. Our data indicate that FMRP and RISC are associated to distinct pools of mRNAs. FMRP, unlike RISC machinery, associates with the pool of mRNAs that eventually goes into stress granules upon cellular stress. Furthermore, we show that FMRP plays a positive role in this process as the lack of FMRP or a point mutant causing a severe fragile X alter stress granule formation. Our data support the proposal that FMRP plays a role in controlling the fate of mRNAs after translation arrest.

SPG11 spastic paraplegia. A new cause of juvenile parkinsonism.

Abstract: Autosomal recessive hereditary spastic paraplegia (AR HSP) with thin corpus callosum (TCC) is a rare neurodegenerative disorder often caused by mutations in the gene encoding for spatacsin at the SPG11 locus on chromosome 15q. The disease is characterized by progressive spastic paraparesis and mental retardation which occur during the first two decades of life and frequently with peripheral neuropathy. Brain magnetic resonance imaging (MRI) reveals typical TCC with periventricular white matter changes. We describe two patients, of Turkish descent, from the same consanguineous family and affected with SPG11 in association with unusual early-onset parkinsonism. Parkinsonism occurred during the very early stages of SPG11 in both patients, being in one the inaugural symptom of the disease presented as a resting tremor with akinesia, rigidity and expressing an initial moderate levodopa-response that progressively weakened. The second patient presented a resting tremor with mild akinesia and no levodopa-response. Both patients were affected with progressive spastic paraparesis which had initially occurred at 15 and 12 years of age, respectively, in association with mild mental retardation and an axonal polyneuropathy. TCC with periventricular white matter changes (PWMC) was evident by MRI and (123)I-ioflupane SPECT was abnormal. Genetic analysis detected for both patients a new c.704_705delAT, p.H235RfsX12 homozygous mutation in SPG11. This report provides evidence that parkinsonism may initiate SPG11-linked HSP TCC and that SPG11 may cause juvenile parkinsonism.

Jean B Dausset, 19 October 1916-6 June 2009.

Abstract: Professor Jean B Dausset, who shared The Nobel Prize in Physiology or Medicine, 1980, with Professors George D Snell and Baruj Benacerraf for his discovery and development of the human major histocompatibility complex (MHC, also commonly called HLA), died in Mallorca, Spain, on 6 June 2009. He was 92 years old. The landmark discoveries of Professor Dausset include agglutination of white blood cells by antibodies from patients who had received blood transfusions, which he realized was due to genetic variation, description of the first leukocyte antigen (now known as HLA-2) and of the first tissue group system (Hu-1, later named HLA), and correlation between graft survival and tissue incompatibility, which was the result of working with volunteer skin donors and recipients. He was active in finding associations of HLA with complex diseases. He was keen on using DNA polymorphisms to characterize HLA. Professors Dausset and E Carosella collaborated in research into the role of HLA-G in human physiology, with implications for immune tolerance in general and pregnancy in particular. Professor Dausset understood the importance of research collaboration and was a dedicated, leading spirit in the HLA Workshops and Conferences, in which competitors collaborate by typing shared tissue resources. Professor Dausset's research achievements were fundamental for the development of tissue typing, which improved the quality of clinical transplantation. He contributed even more to this field by founding France Transplant and France Greffe de Moelle, organizations that are dedicated to bringing donor organs and bone marrow to needy recipients in an efficient and rapid manner. In 1984, Professor Dausset created the Centre d'Etude du Polymorphisme Humain (CEPH), a laboratory, later an internationally renowned genome center, which coordinated the first international genome-mapping collaboration by making available DNA from 40 large reference families (later 61) to researchers throughout the world. By genotyping DNA from the same set of families, it was possible to map the human genome by linkage which determined order of DNA markers along all autosomes, the X chromosome and the X–Y pseudoautosomal region. Knowledge of these chromosome maps, which was made available to the scientific community worldwide, permitted researchers, some of them at the CEPH, to localize the major genes for various genetic disorders to regions of the human genome. Localization of such genes was the first, important step in cloning and identifying them, which was a breakthrough for medical genetics. Furthermore, the linkage maps provided the foundation for the International Genome Project, the physical mapping of the human genome (largely initiated at CEPH), which in turn led to determination of the DNA sequence. The CEPH reference families continue to be used for genomics research. More recently, Professor Dausset collaborated with Professor LL Cavalli-Sforza in developing, at the Foundation, a widely used DNA resource from world populations for research in human population genetics, the HGDP-CEPH Diversity Panel. In 1993, the CEPH became the Foundation Jean Dausset – CEPH, a non-profit research institute funded in part by the Republic of France. Professor Dausset retired as President of the Foundation in 2003; he remained its honorary President until his death. Professor Dausset was a member of the French National Academy of Sciences, professor at the College de France, a foreign member of the National Academy of Sciences, USA, an honorary member of the American Academy of Arts and Sciences, and a member of the founding Council and Vice President of the Human Genome Organization. He received various prestigious prizes, such as the Landsteiner Award and prizes from the Koch and Wolf Foundations. He served on the advisory boards of numerous research institutions. A CEPH collaborator wrote in a tribute to Professor Dausset, ‘He set a standard for cooperative sharing in science with the goal of helping others that has truly revolutionized the ways in which we do our work. All of the genome sharing efforts of sequence and SNPs is based on his CEPH model. It's really not possible to even measure the impact this has had on science.'