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Cascades physiopathologiques dans la maladie de Sanfilippo B

Abstract : Mucopolysaccharidosis type IIIB (Sanfilippo B disease) is a lysosomal storage disease characterized by severe neurological manifestations in children. This rare monogenic disease is caused by a-N­acetylglucosaminidase (NAGLU) deficiency, a lysosomal hydrolase necessary for heparan sulfate (HS) degradation. This deficiency leads to the accumulation of HS saccharides. Mechanisms mediating HS saccharides deleterious effects on brain cells are not well understood. This research provides evidences that neural cell sensing of environment is altered in MPSIIIB cells. Integrins and focal adhesion components are over-recruited and over-activated in deficient mouse astrocytes. Consistently, integrin-dependant cell behavior such as cell polarization and directed migration were defective in affected astrocytes and neural stem cells. HS saccharide clearance, by NAGLU gene transfer, rescues a normal phenotype suggesting that HS saccharides induce focal adhesion formation. Addition of purified HS saccharides on normal astrocytes confirms that extracellular HS saccharides can activate the recruitment of focal adhesion components and provides an in vitro assay to decipher the saccharide code of HS. Otherwise, investigations performed on HeLa cell model, in which NAGLU expression was inhibited by shRNA, showed that accumulation of intracellular storage vesicles, a hallmark of the disease, is due over expression of a cis-Golgi protein. This affects the Golgi morphology and microtubule nucleation and stability. It seems that alterations of environment cell sensing and downstream signaling also modify the dynamic and the structure of cells. We assume that mechanisms deciphered in cell cultures are related to MPSIIIB neuropathology. By affecting cell perception of environmental cues, cell polarity, cell migration and neurite outgrowth, HS saccharides, which accumulate in brain tissues defective for a HS degradation enzyme, likely affect various processes important for accurate cortical maturation.
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Submitted on : Wednesday, November 21, 2012 - 11:02:13 AM
Last modification on : Thursday, April 7, 2022 - 10:10:21 AM
Long-term archiving on: : Friday, February 22, 2013 - 3:47:37 AM


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  • HAL Id : tel-00755417, version 1



Julie Bruyère Bruyere. Cascades physiopathologiques dans la maladie de Sanfilippo B. Médecine humaine et pathologie. Université René Descartes - Paris V, 2012. Français. ⟨NNT : 2012PA05T020⟩. ⟨tel-00755417⟩



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