@article{4e7c2ac26c954927b9dceb981eb3ab64,
title = "Inactivation of Drosophila Apaf-1 related killer suppresses formation of polyglutamine aggregates and blocks polyglutamine pathogenesis",
abstract = "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 files 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.",
author = "Sang, {Tzu Kang} and Chenjian Li and Wencheng Liu and Antony Rodriguez and Abrams, {John M.} and Zipursky, {S. Lawrence} and Jackson, {George R.}",
note = "Funding Information: The authors would like to thank Birgitta Sj{\"o}strand for assistance with TEM, Leslie Thompson and Larry Marsh for the UAS-Q108 and UAS-huntingtin-Q93 fly stocks, Mel Feany for the UAS-ataxin-1-Q82 stock, Pascal Meier for the UAS-DroncC318A and UAS-DroncCARD stocks, the Bloomington Stock Center for miscellaneous fly stocks, the Developmental Hybridoma Studies Bank maintained by the University of Iowa for the Elav antibody, Bruce Hay for the activated Drice antibody and Paul Fisher for the anti-lamin Dm0 antibodies. Thanks also to Carl Johnson and Iris Salecker for critical comments on the manuscript, and to George Lawless for excellent technical assistance. S.L.Z. is an investigator of the Howard Hughes Medical Institute. The authors also would like to express their gratitude to John Mazziotta and Peter Whybrow for their generous support of the UCLA Neurogenetics Program and the Center for Neurobehavioral Genetics. This work was supported by NS002116 and V54 ES012078 (G.R.J.), AG012466 (J.M.A.) and the Cure HD Initiative (G.R.J. and C.L.) and a John J. Wasmuth Postdoctoral Fellowship (T.-K.S.) of the Hereditary Disease Foundation.",
year = "2005",
month = feb,
day = "1",
doi = "10.1093/hmg/ddi032",
language = "English (US)",
volume = "14",
pages = "357--372",
journal = "Human molecular genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "3",
}