Human Molecular Genetics Advance Access originally published online on May 3, 2009
Human Molecular Genetics 2009 18(15):2739-2747; doi:10.1093/hmg/ddp209
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AIP-1 ameliorates β-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's disease model
Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO 80303, USA
* To whom correspondence should be addressed at: Department of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Zip 7660, Omaha, NE 68198, USA. Tel: +1 4025596483; Fax: +1 4025596018; Email: whassan{at}unmc.edu
Received March 1, 2009; Revised April 23, 2009; Accepted April 29, 2009
Multiple neurodegenerative diseases are causally linked to aggregation-prone proteins. Cellular mechanisms involving protein turnover may be key defense mechanisms against aggregating protein disorders. We have used a transgenic Caenorhabditis elegans Alzheimer's disease model to identify cellular responses to proteotoxicity resulting from expression of the human beta amyloid peptide (Aβ). We show up-regulation of aip-1 in Aβ-expressing animals. Mammalian homologues of AIP-1 have been shown to associate with, and regulate the function of, the 26S proteasome, leading us to hypothesize that induction of AIP-1 may be a protective cellular response directed toward modulating proteasomal function in response to toxic protein aggregation. Using our transgenic model, we show that overexpression of AIP-1 protected against, while RNAi knockdown of AIP-1 exacerbated, Aβ toxicity. AIP-1 overexpression also reduced accumulation of Aβ in this model, which is consistent with AIP-1 enhancing protein degradation. Transgenic expression of one of the two human aip-1 homologues (AIRAPL), but not the other (AIRAP), suppressed Aβ toxicity in C. elegans, which advocates the biological relevance of the data to human biology. Interestingly, AIRAPL and AIP-1 contain a predicted farnesylation site, which is absent from AIRAP. This farnesylation site was shown by others to be essential for an AIP-1 prolongevity function. Consistent with this, we show that an AIP-1 mutant lacking the predicted farnesylation site failed to protect against Aβ toxicity. Our results implicate AIP-1 in the regulation of protein turnover and protection against Aβ toxicity and point at AIRAPL as the functional mammalian homologue of AIP-1.