Cerebellar neurons lacking complex gangliosides degenerate in the presence of depolarizing levels of potassium.
Mice engineered to lack GM2/GD2 synthase (GalNAc-T), with resultant deficit of GM2, GD2, and all gangliotetraose gangliosides, were originally described as showing a relatively normal phenotype with only a slight reduction in nerve conduction. However, a subsequent study showed that similar animals suffer axonal degeneration, myelination defects, and impaired motor coordination. We have examined the behavior of cerebellar granule neurons from these neonatal knockouts in culture and have found evidence of impaired capacity for Ca2+ regulation. These cells showed relatively normal behavior when grown in the presence of physiological or moderately elevated K+ but gradually degenerated in the presence of high K+. This degeneration in depolarizing medium was accompanied by progressive elevation of intracellular calcium and onset of apoptosis, phenomena not observed with normal cells. No differences were detected in cells from normal vs. heterozygous mice. These findings suggest that neurons from GalNAc-T knockout mice are lacking a calcium regulatory mechanism that is modulated by one or more of the deleted gangliosides, and they support the hypothesis that maintenance of calcium homeostasis is one function of complex gangliosides during, and perhaps subsequent to, neuronal development.
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Department of Neurosciences, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA.
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002855:Chromatography, Thin Layer; D005732:Gangliosides / Q000032:analysis / Q000172:deficiency*; D017353:Gene Deletion; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017350:N-Acetylgalactosaminyltransferases / Q000172:deficiency* / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology*
D005732:Gangliosides; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase; D011188:Potassium; D002118:Calcium