ArticlePLoS genetics2010
Mice doubly-deficient in lysosomal hexosaminidase A and neuraminidase 4 show epileptic crises and rapid neuronal loss.
Article in PLoS genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 43 citations in OpenAlex.
- B4Galnt1 Deficiency Reverses Severe Neurological Symptoms in a Mouse Model of Tay-Sachs Disease.Neuromolecular medicine · 2026Article
- Article
- Characterization of a phenotypically severe animal model for human AB-Variant GM2 gangliosidosis.Frontiers in molecular neuroscience · 2023Article
- Sialidase neu4 deficiency is associated with neuroinflammation in mice.Glycoconjugate journal · 2021Article
- Head-Only Stunning of Turkeys Part 2: Subjective and Objective Assessment of the Application of AC and DC Waveforms.Animals : an open access journal from MDPI · 2021Article
- GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early onset Tay-Sachs disease.Journal of neuroinflammation · 2020Article
- Substrate Reduction Therapy for Sandhoff Disease through Inhibition of Glucosylceramide Synthase Activity.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- Keeping it trim: roles of neuraminidases in CNS function.Glycoconjugate journal · 2018Review
- Mice with Catalytically Inactive Cathepsin A Display Neurobehavioral Alterations.Behavioural neurology · 2017Article
- Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease.Human gene therapy · 2016Article
- Construction of a hybrid β-hexosaminidase subunit capable of forming stable homodimers that hydrolyze GM2 ganglioside in vivo.Molecular therapy. Methods & clinical development · 2016Article
- Neuraminidase-1 contributes significantly to the degradation of neuronal B-series gangliosides but not to the bypass of the catabolic block in Tay-Sachs mouse models.Molecular genetics and metabolism reports · 2015Article
- Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model.Brain : a journal of neurology · 2015Article
- The glycosphingolipid hydrolases in the central nervous system.Molecular neurobiology · 2014Review
- Identification of Selective Nanomolar Inhibitors of the Human Neuraminidase, NEU4.ACS medicinal chemistry letters · 2013Article
- Sialidase NEU4 hydrolyzes polysialic acids of neural cell adhesion molecules and negatively regulates neurite formation by hippocampal neurons.The Journal of biological chemistry · 2012Article
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16 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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