Huntingtin toxicity

Abstract

A new study is challenging the role of cleavage of the huntingtin protein (HD) by caspase proteases in the pathology of Huntington's disease. The ‘toxic peptide theory’ suggests that proteolytic cleavage of mutant HD generates protein fragments, containing the expanded poyglutamine region, that sequester important cellular proteins. Now, Roy Dyer and Cynthia McMurray at the Mayo Clinic and Foundation (Rochester, Minnesota), published online in Nature Genetics in October, report the unexpected finding that mutated HD protein is more resistant to proteolysis than the normal form. They examined extracts from human diseased tissue and found that there were less cleavage products and that polypeptide fragments came from the normal HD protein. They propose a model in which the inhibition of proteolysis of the mutant HD form results in the sequestering of important targets, including normal HD, leading to aggregation and toxicity. JW