Human Molecular Genetics Advance Access originally published online on December 8, 2004
Human Molecular Genetics 2005 14(3):357-372; doi:10.1093/hmg/ddi032
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Human Molecular Genetics, Vol. 14, No. 3 © Oxford University Press 2005; all rights reserved
Inactivation of Drosophila Apaf-1 related killer suppresses formation of polyglutamine aggregates and blocks polyglutamine pathogenesis
1Neurogenetics Program, Department of Neurology, 2Department of Biological Chemistry and Howard Hughes Medical Institute, 3Brain Research Institute, 4Center for Neurobehavioral Genetics, Neuropsychiatric Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA, 5Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA and 6Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
* To whom correspondence should be addressed at: Neurogenetics Program, Department of Neurology, 710 Westwood Plaza, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Tel: +1 3107945638; Fax: +1 3102672473; Email: grjackson{at}mednet.ucla.edu
Received September 7, 2004; Revised November 10, 2004; Accepted November 26, 2004
Huntington's disease (HD) is caused by expansion of a polyglutamine tract near the N-terminal of huntingtin. Mutant huntingtin forms aggregates in striatum and cortex, where extensive cell death occurs. We used a Drosophila polyglutamine peptide model to assess the role of specific cell death regulators in polyglutamine-induced cell death. Here, we report that polyglutamine-induced cell death was dramatically suppressed in flies lacking Dark, the fly homolog of human Apaf-1, a key regulator of apoptosis. Dark appeared to play a role in the accumulation of polyglutamine-containing aggregates. Suppression of cell death, caspase activation and aggregate formation were also observed when mutant huntingtin exon 1 was expressed in homozygous dark mutant animals. Expanded polyglutamine induced a marked increase in expression of Dark, and Dark was observed to colocalize with ubiquitinated protein aggregates. Apaf-1 also was found to colocalize with huntingtin-containing aggregates in a murine model and HD brain, suggesting a common role for Dark/Apaf-1 in polyglutamine pathogenesis in invertebrates, mice and man. These findings suggest that limiting Apaf-1 activity may alleviate both pathological protein aggregation and neuronal cell death in HD.
Present address: The Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
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