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https://hdl.handle.net/11147/2676
Title: | Mice Doubly-deficient in lysosomal hexosaminidase a and neuraminidase 4 show epileptic crises and rapid neuronal loss | Authors: | Seyrantepe, Volkan Lema, Pablo Caqueret, Aurore Dridi, Larbi Hadj, Samar Bel Carpentier, Stephane Boucher, Francine Levade, Thierry Carmant, Lionel Gravel, Roy A. Hamel, Edith Vachon, Pascal Di Cristo, Graziella Michaud, Jacques L. Morales, Carlos R. Pshezhetsky, Alexey V. |
Keywords: | Unclassified drug Animal cell Cerebral cortex Motor activity Electroencephalography Tay Sachs disease Neurons |
Publisher: | Public Library of Science | Source: | Seyrantepe, V., Lema, P., Caqueret, A., Dridi, L., Hadj, S. B., Carpentier, S, ... Pshezhetsky, A. V. (2010). Mice Doubly-deficient in lysosomal hexosaminidase a and neuraminidase 4 show epileptic crises and rapid neuronal loss. PLoS Genetics, 6(9). doi:10.1371/journal.pgen.1001118 | Abstract: | Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the a-subunit of lysosomal β-hexosaminidase A, which converts GM2 to GM3 ganglioside. Hexa-/- mice, depleted of b-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise GM2 ganglioside via a lysosomal sialidase into glycolipid GA2, which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4-/-;Hexa-/-) show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa-/- or Neu4-/- siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating GM2 ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa-/- mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa-/- mice. | URI: | http://doi.org/10.1371/journal.pgen.1001118 http://hdl.handle.net/11147/2676 |
ISSN: | 1553-7390 1553-7404 |
Appears in Collections: | Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection |
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