Huda Zoghbi, MD
Jan and Dan Duncan Neurological Research Institute
Baylor College of Medicine
Title: A cross-species genetic screen to identify targets that regulate the steady state levels of tau.
Abstract: Alzheimer disease (AD) is characterized by the deposition of amyloid plaques and the accumulation of neurofibrillary tangles, products of APP processing and tau hyperphosphorylation respectively. Several studies demonstrate that reduction of tau is therapeutically beneficial in AD mouse models. This evidence prompted us to hypothesize that modest reduction in the endogenous levels of tau proteins would delay the onset and retard progression of disease. Using a multi-pronged approach we seek to harness innate mechanisms within the cell for regulating tau to find new therapeutic targets and to gain insight in AD pathogenesis. We will identify these pathways using an unbiased, high-throughput RNA interference screen of 7,787 druggable genes. We will employ two different assay systems in parallel (human neuronal cell lines and Drosophila expressing human tau) to identify those proteins whose reduction results in lower levels of tau, and rescue neuronal degeneration phenotypes in Drosophila. Candidates identified in cells and Drosophila will be mapped into an in silco network of modifier genes using computational analyses to pinpoint common pathways converging on the modulation of tau levels. Preliminary studies have revealed new modulators of tau that we are verifying in AD mouse models. We are also testing tool compounds that target or most promising hits. The major goal of this project is to discover new therapeutic targets for Alzheimer’s disease. We propose a research program centered on genes and genetic networks that control tau levels using innovative orthoganol screens of the “druggable” genome. Assembly of the results into canonical regulatory pathways, together with validation using known small molecules, should greatly improve our understanding of the molecular underpinnings of this disorder and accelerate the discovery of new therapeutic leads for the treatment of Alzheimer’s disease.