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 approximate to1.5% of brain dry weight) their func tions have remained obscure. We report that mice engineered to lack a key e nzyme in complex ganglioside biosynthesis (GM2/GD2 synthase), and which exp ress only the simple ganglioside molecular species GM3 and GD3, develop sig nificant and progressive behavioral neuropathies, including deficits in ref lexes, strength, coordination, and balance. Quantitative indices of motor a bilities, applied at 8 and 12 months of age, also revealed progressive gait disorders in complex ganglioside knockout mice compared to controls, inclu ding reduced stride length, stride width, and increased hindpaw print lengt h as well as a marked reduction in rearing. Compared to controls, null muta nt mice tended to walk in small labored movements. Twelve-month-old complex ganglioside knockout mice also displayed significant incidence of tremor a nd catalepsy. These comprehensive neurobehavioral studies establish an esse ntial role for complex gangliosides in the maintenance of normal neural phy siology in mice, consistent with a role in maintaining axons and myelin (Sh eikh, K. A., J. Sun, Y. Liu, H. Kawai, T. O. Crawford, R. L. Proia, J. W. G riffin, 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 cer tain neural degenerative diseases, (C) 2000 Academic Press.