MYELINATION IN THE ABSENCE OF GALACTOCEREBROSIDE AND SULFATIDE - NORMAL STRUCTURE WITH ABNORMAL FUNCTION AND REGIONAL INSTABILITY

The vertebrate nervous system is characterized by ensheathment of axon s with myelin, a multilamellar membrane greatly enriched in the galact olipid galactocerebroside (GalC) and its sulfated derivative sulfatide . We have generated mice lacking the enzyme UDP-galactose:ceramide gal actosyltransferase (CGT), which is required for GalC synthesis. CGT-de ficient mice do not synthesize GalC or sulfatide but surprisingly form myelin containing glucocerebroside, a lipid not previously identified in myelin. Microscopic and morphometric analyses revealed myelin of n ormal ultrastructural appearance, except for slightly thinner sheaths in the ventral region of the spinal cord. Nevertheless, these mice exh ibit severe generalized tremoring and mild ataxia, and electrophysiolo gical analysis showed conduction deficits consistent with reduced insu lative capacity of the myelin sheath. Moreover, with age, CGT-deficien t mice develop progressive hindlimb paralysis and extensive vacuolatio n of the ventral region of the spinal cord. These results indicate tha t GalC and sulfatide play important roles in myelin function and stabi lity.