Caspase Cleavage of Mutant Huntingtin Precedes Neurodegeneration in Huntington's Disease

摘要: Huntington's disease (HD) results from polyglutamine expansion in huntingtin (htt), a protein with several consensus caspase cleavage sites. Despite the identification of htt fragments brain, it has not been shown conclusively that is cleaved by caspases vivo. Furthermore, no study addressed when occurs respect to onset neurodegeneration. Using antibodies detect only caspase-cleaved htt, we demonstrate vivo specifically at site amino acid 552. We control human brain as well HD brains early grade neuropathology, including one homozygote. Cleaved also seen wild-type and transgenic mouse before These suggest may be normal physiological event. However, HD, mutant would release N-terminal potential for increased toxicity accumulation caused presence expanded tract. were detected most abundantly cortical projection neurons, suggesting these neurons lead corticostriatal dysfunction an event pathogenesis HD.