Combined deficiencies of endosomal ganglioside neuraminidases 3 and 4 in mice cause lysosomal GM3 gangliosidosis

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By regulating recognition, signaling and physiology of neurons, gangliosides are essential to CNS function.The composition of gangliosides in the brain changes during development and aging being regulated by neuraminidases presumably, which cleave their terminal sialic acid residues.Two mammalian neuraminidases, Neu3 and Neu4 are major candidates for processing brain gangliosides, however, the corresponding knockout mice showed no changes in brain ganglioside metabolism or deficits in brain function.To elucidate the physiological functions of Neu4 and Neu3 in the brain, we generated a gene-targeted mouse strain devoid of both enzymes.At the age of 10 months the mice showed deficits in spatial and short-term memory, whereas neuraminidase activity against gangliosides in their brain tissues was below detection levels.GM3 ganglioside was stored in lysosomes of neurons, microglia and vascular pericytes and GM1-ganglioside decreased in the axons.The number of astrocytes and activated microglia was increased, consistent with neuroinflammation.Cultured hippocampal and cortical neurons also showed reduced levels of GM1 ganglioside in the axons and impaired neuritogenesis.Our data provide evidence that Neu3 and Neu4 have unique roles in the regulation of brain ganglioside composition essential for CNS function: Neu4 generates the neuronal GM1 necessary for axon growth whereas Neu3 catabolizes GM3.