A functional role for complex gangliosides: motor deficits in GM2/GD2 synthase knockout mice.

Although gangliosides are abundant molecular determinants on all vertebrate nerve cells (comprising approximately 1.5% of brain dry weight) their functions have remained obscure. We report that mice engineered to lack a key enzyme in complex ganglioside biosynthesis (GM2/GD2 synthase), and which express only the simple ganglioside molecular species GM3 and GD3, develop significant and progressive behavioral neuropathies, including deficits in reflexes, strength, coordination, and balance. Quantitative indices of motor abilities, applied at 8 and 12 months of age, also revealed progressive gait disorders in complex ganglioside knockout mice compared to controls, including reduced stride length, stride width, and increased hindpaw print length as well as a marked reduction in rearing. Compared to controls, null mutant mice tended to walk in small labored movements. Twelve-month-old complex ganglioside knockout mice also displayed significant incidence of tremor and catalepsy. These comprehensive neurobehavioral studies establish an essential role for complex gangliosides in the maintenance of normal neural physiology in mice, consistent with a role in maintaining axons and myelin (Sheikh, K. A. , J. Sun, Y. Liu, H. Kawai, T. O. Crawford, R. L. Proia, J. W. Griffin, and R. L. Schnaar. 1999. Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc. Natl. Acad. Sci. USA 96: 7532-7537), and may provide insights into the mechanisms underlying certain neural degenerative diseases.