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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
Tay Sachs disease
Issue Date: Sep-2010
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.
ISSN: 1553-7390
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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