Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Gangliosides (sialylated glycolipids) are vital for central nervous system (CNS) neuronal function, regulating recognition and signaling.
• Metabolic disorders in ganglioside processing cause severe neurological conditions like gangliosidoses, characterized by neurodegeneration and neuroinflammation.

Purpose of the Study:

• To investigate the role of mammalian neuraminidases 3 and 4 in the catabolic processing of brain gangliosides.
• To elucidate the in vivo consequences of neuraminidase 3 and 4 deficiency in the CNS.

Main Methods:

• Generation and analysis of neuraminidase 3 and 4 double-knockout mice.
• Biochemical and histological examination of brain tissues to assess ganglioside storage, neuroinflammation, and neuronal morphology.
• Evaluation of neuraminidase 3's impact on a mouse model of Tay-Sachs disease.

Main Results:

• Neuraminidase 3 and 4 double-knockout mice exhibit G_M3 ganglioside accumulation in microglia, pericytes, and neurons, leading to micro- and astrogliosis, neuroinflammation, lipofuscin bodies, and memory deficits.
• These mice show reduced G_M1 ganglioside levels and myelin in neuronal axons, with impaired neuritogenesis in vitro.
• Neuraminidase 3 deficiency exacerbated G_M2 storage in a Tay-Sachs disease model, suggesting a role in bypassing hexosaminidase A deficiency.

Conclusions:

• Neuraminidases 3 and 4 are essential for the in vivo catabolism of brain gangliosides.
• Their function is critical for preventing ganglioside accumulation, lipofuscin body formation, and maintaining normal neuronal function and cognitive abilities.
• These enzymes represent potential therapeutic targets for managing gangliosidoses and related neurological disorders.