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Inactivation of Drosophila Apaf-1 related killer suppresses formation of polyglutamine aggregates and blocks polyglutamine pathogenesis.

TitleInactivation of Drosophila Apaf-1 related killer suppresses formation of polyglutamine aggregates and blocks polyglutamine pathogenesis.
Publication TypeJournal Article
Year of Publication2005
AuthorsSang T-K, Li C, Liu W, Rodriguez A, Abrams JM, S Zipursky L, Jackson GR
JournalHum Mol Genet
Volume14
Issue3
Pagination357-72
Date Published2005 Feb 1
ISSN0964-6906
KeywordsAnimals, Apoptotic Protease-Activating Factor 1, Brain, Caspase 3, Caspases, Cell Death, Drosophila, Drosophila Proteins, Exons, Eye, Humans, Huntington Disease, Mice, Mice, Mutant Strains, Microscopy, Electron, Mutation, Nerve Degeneration, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Proteins
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 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.

DOI10.1093/hmg/ddi032
Alternate JournalHum. Mol. Genet.
PubMed ID15590702
Grant ListAG012466 / AG / NIA NIH HHS / United States
NS002116 / NS / NINDS NIH HHS / United States
R01 GM072124 / GM / NIGMS NIH HHS / United States
R01 GM072124-14A1 / GM / NIGMS NIH HHS / United States
V45 ES012078 / ES / NIEHS NIH HHS / United States