Deciphering a yeast model for beta-amyloid toxicity

A systems biology approach to reveal the molecular basis of beta-amyloid toxicity implicated in Alzheimer disease Final report Principal Investigators: Esti Yeger-Lotem & Susan Lindquist ABSTRACT Alzheimer disease (AD) is the most common neurodegenerative disorder and despite immense efforts remains incurable. β-amyloid (Aβ) peptides appear in brain plaques in all forms of AD, and familial AD indicates that they are causal for the disease. A comprehensive understanding of the cellular processes that underlie Aβ toxicity is essential for opening new avenues for treatment.

In an effort to elucidate these processes, the Lindquist lab developed a new yeast model of Aβ toxicity amenable to high-throughput genetic screens and mRNA profiling assays. In a previous collaboration with the Lindquist lab we reported ResponseNet, a computational network-optimization approach that integrates diverse large-scale data using known molecular interactions. Applied to a yeast model of alpha-synuclein toxicity implicated in Parkinson disease, ResponseNet successfully mapped previously unknown as well as recognized disease-related pathways. Here we combined our state-of-the-art computational and experimental approaches to reveal pathways underlying Aβ toxicity.

The specific aims of the research were: 1. Update ResponseNet and tailor it to new Aβ data.

2. Apply ResponseNet to identify processes involved in Aβ toxicity.

3. Validate promising predictions experimentally.

We reported a freely-available ResponseNet web-server. Using ResponsNet we predicted the involvement of several cellular pathways in Aβ toxicity, including TOR signaling and endocytosis pathways that have been previously implicated in AD. We found that deletion of the protein Rvs167 whose involvement was predicted by ResponseNet markedly affected Aβ toxicity. Notably, the human homolog of Rvs167, amphiphysin 1 (AMPH) protein, functions in a heterodimer with amphiphysin 2 (BIN1), a validated AD risk factor.