RT Journal Article
SR Electronic
T1 Caspase Cleavage of Mutant Huntingtin Precedes Neurodegeneration in Huntington's Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7862
OP 7872
DO 10.1523/JNEUROSCI.22-18-07862.2002
VO 22
IS 18
A1 Cheryl L. Wellington
A1 Lisa M. Ellerby
A1 Claire-Anne Gutekunst
A1 Danny Rogers
A1 Simon Warby
A1 Rona K. Graham
A1 Odell Loubser
A1 Jeremy van Raamsdonk
A1 Roshni Singaraja
A1 Yu-Zhou Yang
A1 Juliette Gafni
A1 Dale Bredesen
A1 Steven M. Hersch
A1 Blair R. Leavitt
A1 Sophie Roy
A1 Donald W. Nicholson
A1 Michael R. Hayden
YR 2002
UL http://www.jneurosci.org/content/22/18/7862.abstract
AB 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 in the brain, it has not been shown conclusively that htt is cleaved by caspases in vivo. Furthermore, no study has addressed when htt cleavage occurs with respect to the onset of neurodegeneration. Using antibodies that detect only caspase-cleaved htt, we demonstrate that htt is cleaved in vivo specifically at the caspase consensus site at amino acid 552. We detect caspase-cleaved htt in control human brain as well as in HD brains with early grade neuropathology, including one homozygote. Cleaved htt is also seen in wild-type and HD transgenic mouse brains before the onset of neurodegeneration. These results suggest that caspase cleavage of htt may be a normal physiological event. However, in HD, cleavage of mutant htt would release N-terminal fragments with the potential for increased toxicity and accumulation caused by the presence of the expanded polyglutamine tract. Furthermore, htt fragments were detected most abundantly in cortical projection neurons, suggesting that accumulation of expanded htt fragments in these neurons may lead to corticostriatal dysfunction as an early event in the pathogenesis of HD.