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Vol. 96, Issue 1, 179-184, January 5, 1999
* Cancer Center and § Molecular Neurogenetics Unit, Edited by H. Robert Horvitz, Massachusetts Institute of Technology,
Cambridge, MA, and approved November 6, 1998 (received for review August 21, 1998)
The effect of expressing human huntingtin fragments containing
polyglutamine (polyQ) tracts of varying lengths was assessed in
Caenorhabditis elegans ASH sensory neurons
in young and old animals. Expression of a huntingtin fragment
containing a polyQ tract of 150 residues (Htn-Q150) led to progressive
ASH neurodegeneration but did not cause cell death. Progressive cell
death and enhanced neurodegeneration were observed in ASH neurons that
coexpressed Htn-Q150 and a subthreshold dose of a toxic
OSM-10::green fluorescent protein (OSM-10::GFP) fusion protein.
Htn-Q150 huntingtin protein fragments formed protein aggregates in ASH
neurons, and the number of ASH neurons containing aggregates increased
as animals aged. ASH neuronal cell death required ced-3
caspase function, indicating that the observed cell death is
apoptotic. Of interest, ced-3 played a critical
role in Htn-Q150-mediated neurodegeneration but not in
OSM10::GFP-mediated ASH neurodegeneration. ced-3
function was important but not essential for the formation of protein
aggregates. Finally, behavioral assays indicated that ASH neurons,
coexpressing Htn-Q150 and OSM10::GFP, were functionally impaired at
3 days before the detection of neurodegeneration, cell death, and
protein aggregates.
Copyright © 1999 by The National Academy of Sciences 0027-8424/99/96179-6$2.00/0
Genetics
Polyglutamine-mediated dysfunction and apoptotic death of
a Caenorhabditis elegans sensory neuron
,
,,,,¶
Department of
Pathology, Harvard Medical School, Charlestown, MA 02129
P.W.F. and J.R.A. contributed equally to this work.
¶
To whom reprint requests should be addressed at: Cancer
Center, Massachusetts General Hospital East, Building 149-7202, Charlestown, MA 02129. e-mail: hart{at}helix.mgh.harvard.edu.
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