The researchers extracted huntingtin from brains of normal and diseased humans after death. Using antibodies that distinguish between normal and expanded protein, they showed that, in normal brain extracts, wildtype huntingtin is mainly soluble and exists as both full-length protein and N-terminal fragments. In contrast, poly-Q huntingtin from diseased brains forms aggregates without evidence of proteolysis. Furthermore, N-terminal fragments of wildtype huntingtin in diseased brains aggregates with full-length poly-Q huntingtin.

Why polyQ huntingtin resists proteolysis is unclear. However, caspase-3 activation initiated the cleavage of wildtype N-terminal huntingtin but not of mutant huntingtin, and the presence of mutant huntingtin appears to protect wild-type protein from proteolysis in various cultured cell types.

The authors suggest that the resistance to proteolysis allows expanded huntingtin to accumulate and to sequester normal huntingtin or other targets in protein aggregates. This, in turn, is predicted to lead to energy deficit and caspase activation. "This is an interesting paper that proposes the complete opposite of the toxic fragment hypothesis," comments Marian DiFiglia, professor of neurology at Harvard Medical School, "it is going to get people thinking a lot more about the role of proteolysis."-Tom Fagan.

Reference:Dyer RB and McMurray T. Mutant protein in Huntington's disease is resistant to proteolysis in affected brain. Nature Genetics 2001 October 15. Abstract