19 October 2001. Another theory to explain Huntington's suggests that proteolysis
of polyglutamine-expanded (poly-Q) huntingtin by caspase enzymes generates toxic
N-terminal peptide fragments. Though caspases are required for apoptosis induction
by mutated huntingtin, this theory has proven hard to test. Now, Roy Dyer and
Cynthia McMurray from the Mayo Clinic in Rochester, Minnesota, report in a Nature
Genetics article, published online last Monday, that poly-Q huntingtin is, in
fact, resistant to proteolysis and appears to precipitate protein aggregation
in affected tissues.
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