Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington’s disease model
Open Access
- 30 April 2009
- journal article
- Published by The Company of Biologists in Disease Models & Mechanisms
- Vol. 2 (5-6), 247-266
- https://doi.org/10.1242/dmm.000653
Abstract
SUMMARY: A polyglutamine expansion in the huntingtin (HTT) gene causes neurodegeneration in Huntington’s disease (HD), but the in vivo function of the native protein (Htt) is largely unknown. Numerous biochemical and in vitro studies have suggested a role for Htt in neuronal development, synaptic function and axonal trafficking. To test these models, we generated a null mutant in the putative Drosophila HTT homolog (htt, hereafter referred to asdhtt) and, surprisingly, found that dhtt mutant animals are viable with no obvious developmental defects. Instead, dhtt is required for maintaining the mobility and long-term survival of adult animals, and for modulating axonal terminal complexity in the adult brain. Furthermore, removing endogenous dhtt significantly accelerates the neurodegenerative phenotype associated with a Drosophila model of polyglutamine Htt toxicity (HD-Q93), providing in vivo evidence that disrupting the normal function of Htt might contribute to HD pathogenesis.Keywords
This publication has 83 references indexed in Scilit:
- Phylogenetic Comparison of Huntingtin Homologues Reveals the Appearance of a Primitive polyQ in Sea UrchinMolecular Biology and Evolution, 2008
- Evidence of off-target effects associated with long dsRNAs in Drosophila melanogaster cell-based assaysNature Methods, 2006
- Genome-Wide Transcriptional Changes Associated with Enhanced Activity in the Drosophila Nervous SystemNeuron, 2005
- Comparison of ARM and HEAT protein repeatsJournal of Molecular Biology, 2001
- Evidence for a recruitment and sequestration mechanism in Huntington'sdiseasePhilosophical Transactions Of The Royal Society B-Biological Sciences, 1999
- Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansionNature Genetics, 1997
- HEAT repeats in the Huntington's disease proteinNature Genetics, 1995
- A Component of Calcium-activated Potassium Channels Encoded by the Drosophila slo LocusScience, 1991
- Huntingtons DiseaseNew England Journal of Medicine, 1986
- On the relationship between senescence and age-related changes in two wild-type strains of Drosophila melanogasterExperimental Gerontology, 1978