Smith-Lemli-Opitz syndrome (SLOS) is a developmental disorder caused by mutations in the gene encoding the last enzyme in the cholesterol biosynthetic pathway. The mutations result in reduced levels of cholesterol and accumulation of the precursor 7-DHC, which can be oxidized in free radical-mediated reactions to oxysterols such as DHCEO.
Zeljka Korade, Ph.D., Ned Porter, Ph.D., and colleagues explored the consequences of 7-DHC and DHCEO accumulation in the brain tissue of a mouse model for SLOS. They found that cholesterol, 7-DHC and DHCEO have region-specific distributions in the brain, suggesting that the midbrain and cortex are the primary sites of vulnerability. They also showed that an oxysterol mixture is toxic to neurons and that DHCEO alone accelerates differentiation and changes the growth pattern of cortical neurons.
The findings, reported in the March issue of Neurobiology of Disease, suggest that 7-DHC oxidative metabolites contribute to altered neural development in SLOS. The results imply that using antioxidants to reduce oxidative stress may be a beneficial treatment for SLOS.
This research was supported by grants from the National Institute of Mental Health, the National Institute of Environmental Health Sciences, and the National Institute of Child Health and Human Development of the National Institutes of Health.
