Skip Navigation



Human Molecular Genetics Advance Access published online on December 8, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi032
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Material
Right arrow All Versions of this Article:
14/3/357    most recent
ddi032v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Sang, T.-K.
Right arrow Articles by Jackson, G. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sang, T.-K.
Right arrow Articles by Jackson, G. R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, Vol. 14, No. 3 © Oxford University Press 2005; all rights reserved

Article

Inactivation of Drosophila Apaf-1 Related Killer Suppresses Formation of Polyglutamine Aggregates and Blocks Polyglutamine Pathogenesis

Tzu-Kang Sang 1, Chenjian Li 2, Wencheng Liu 2, Antony Rodriguez 3, John M. Abrams 4, S. Lawrence Zipursky 5, and George R. Jackson 6*

1 Neurogenetics Program, Department of Neurology, 710 Westwood Plaza, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
2 Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA
3 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; The Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK
4 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
5 Department of Biological Chemistry and Howard Hughes Medical Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
6 Neurogenetics Program, Department of Neurology, 710 Westwood Plaza, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Center for Neurobehavioral Genetics, Neuropsychiatric Instititute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA

* To whom correspondence should be addressed.
George R. Jackson, E-mail: grjackson{at}mednet.ucla.edu


  Abstract

Huntington's disease (HD) is caused by expansion of a polyglutamine tract near the amino terminus 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 in 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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
J. L. Marsh, T. Lukacsovich, and L. M. Thompson
Animal Models of Polyglutamine Diseases and Therapeutic Approaches
J. Biol. Chem., March 20, 2009; 284(12): 7431 - 7435.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Chatterjee, T.-K. Sang, G. M. Lawless, and G. R. Jackson
Dissociation of tau toxicity and phosphorylation: role of GSK-3{beta}, MARK and Cdk5 in a Drosophila model
Hum. Mol. Genet., January 1, 2009; 18(1): 164 - 177.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J.-C. Lievens, M. Iche, M. Laval, C. Faivre-Sarrailh, and S. Birman
AKT-sensitive or insensitive pathways of toxicity in glial cells and neurons in Drosophila models of Huntington's disease
Hum. Mol. Genet., March 15, 2008; 17(6): 882 - 894.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
T.-K. Sang, H.-Y. Chang, G. M. Lawless, A. Ratnaparkhi, L. Mee, L. C. Ackerson, N. T. Maidment, D. E. Krantz, and G. R. Jackson
A Drosophila Model of Mutant Human Parkin-Induced Toxicity Demonstrates Selective Loss of Dopaminergic Neurons and Dependence on Cellular Dopamine
J. Neurosci., January 31, 2007; 27(5): 981 - 992.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.