EXPRESSION OF NORMAL AND MUTANT HUNTINGTIN IN THE DEVELOPING BRAIN

Huntington's disease (HD) is caused by a genetic mutation that results in a polyglutamine expansion in huntingtin. The time course of neuron al loss in the HD striatum and other affected brain regions before the onset of symptoms is unknown. To determine the potential influence of huntingtin on brain development, we examined its expression in the de veloping mouse and in human control and HD brain. By Western blot, hun tingtin was detected throughout the adult mouse brain and at all stage s of embryonic and postnatal brain development. The protein increased significantly between postnatal day 7 (P7) and P15, which marks a peri od of active neuronal differentiation and enhanced sensitivity to exci totoxic injury in the rodent striatum. Immunoreactivity was found in n eurons throughout the brain and localized mostly to the somatodendriti c cytoplasm and to axons in fiber bundles. Staining was variable in di fferent groups of neurons and within the same cell population. In deve loping brain, huntingtin was limited primarily to neuronal perikarya. Increased immunoreactivity in large neurons followed the gradient of n eurogenesis and appeared in the basal forebrain and brainstem by embry onic days 15-17, in regions of cortex by P0-P1, and in the striatum by P7. In human brain at midgestation (19-21 weeks), huntingtin was dete cted in all regions. The brain of a 10-week-old infant with the expand ed HD allele expressed a higher molecular weight mutant form of huntin gtin at levels comparable to those of the wild-type protein. Thus, mut ant huntingtin is expressed before neuronal maturation is complete. Re sults suggest that huntingtin has an important constitutive role in ne urons during brain development, that heterogeneity in neuronal express ion of the protein is developmentally regulated, and that the intraneu ronal distribution of huntingtin increases in parallel with neuronal m aturation. The presence of mutant huntingtin in the immature HD brain raises the possibility that neurons may be affected during brain devel opment and possibly in the postnatal period when vulnerability to exci totoxic injury is at its peak.