AIP-1 ameliorates β-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's disease model

Abstract

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 (Abeta). We show up-regulation of aip-1 in Abeta-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, Abeta toxicity. AIP-1 overexpression also reduced accumulation of Abeta 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 Abeta 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 Abeta toxicity. Our results implicate AIP-1 in the regulation of protein turnover and protection against Abeta toxicity and point at AIRAPL as the functional mammalian homologue of AIP-1.

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…aip-1/ AIRAP binds to the 19S increasing proteasome activity and clearance of damaged proteins 181 . Notably, aip-1/AIRAP ameliorates Ab and polyQ toxicity 182,183 . Moreover, skn-1 and its mammalian orthologues Nrf1 and Nrf2 upregulate the expression of proteasomal genes in response to proteasome inhibition and oxidative stress 39 .…”

Assaying &beta;-amyloid Toxicity using a Transgenic <em>C. elegans</em> Model

“…One particularly useful C. elegans model employs a temperature-sensitive mutation in the mRNA surveillance system to engineer temperatureinducible muscle expression of an Aβ transgene, resulting in a reproducible paralysis phenotype upon temperature upshift . Treatments that counter Aβ toxicity in this model [e.g., expression of a protective transgene (Hassan et al 2009) or exposure to Ginkgo biloba extracts (Wu et al 2006)] reproducibly alter the rate of paralysis induced by temperature upshift of these transgenic worms. Here we describe our protocol for measuring the rate of paralysis in this transgenic C. elegans model, with particular attention to experimental variables that can influence this measurement.…”

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

“…This induction of Ab 42 leads to a highly reproducible paralysis phenotype, in which all induced animals become paralyzed within 28 hr of temperature upshift. This model has previously been used to investigate gene expression changes in response to Ab accumulation (Link et al 2003) and the role of specific genes (Fonte et al 2008;Hassan et al 2009) and autophagy (Florez-McClure et al 2007) in countering Ab toxicity. Here we employ this model to investigate candidate genes and pathways that might play a significant role in the protective effects of coffee.…”