title: Mice doubly-deficient in lysosomal hexosaminidase A and neuraminidase 4 show epileptic crises and rapid neuronal loss.
abstract: Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts G(M2) to G(M3) ganglioside. Hexa(-/-) mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise G(M2) ganglioside via a lysosomal sialidase into glycolipid G(A2), 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 G(M2) 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.
authors.affiliation: Division of Medical Genetics, Centre Hospitalière Universitaire Sainte-Justine, University of Montréal, Montréal, Quebec, Canada.
authors.forename: Volkan
authors.initials: V
authors.lastname: Seyrantepe
authors.forename: Pablo
authors.initials: P
authors.lastname: Lema
authors.forename: Aurore
authors.initials: A
authors.lastname: Caqueret
authors.forename: Larbi
authors.initials: L
authors.lastname: Dridi
authors.forename: Samar
authors.initials: S
authors.lastname: Bel Hadj
authors.forename: Stephane
authors.initials: S
authors.lastname: Carpentier
authors.forename: Francine
authors.initials: F
authors.lastname: Boucher
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.forename: Lionel
authors.initials: L
authors.lastname: Carmant
authors.forename: Roy A
authors.initials: RA
authors.lastname: Gravel
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
authors.forename: Pascal
authors.initials: P
authors.lastname: Vachon
authors.forename: Graziella
authors.initials: G
authors.lastname: Di Cristo
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Morales
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D004569:Electroencephalography; D004827:Epilepsy / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D005678:G(M2) Ganglioside / Q000378:metabolism; D055786:Gene Knockout Techniques; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D007858:Learning / Q000502:physiology; D008247:Lysosomes / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009439:Neuraminidase / Q000172:deficiency* / Q000378:metabolism; D009474:Neurons / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D054820:beta-Hexosaminidase alpha Chain / Q000378:metabolism*
chemical_list: D005678:G(M2) Ganglioside; C481539:Neu4 protein, mouse; D009439:Neuraminidase; D054820:beta-Hexosaminidase alpha Chain