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Penn researchers find potential in yeast for selecting Lou Gehrig's disease drugs
Date:4/17/2008

PHILADELPHIA - Researchers from the University of Pennsylvania School of Medicine are developing a novel approach to screen for drugs to combat neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, using yeast cells. In recent months a number of mutations have been found in a disease protein called TDP-43, which is implicated in ALS and certain types of frontotemporal dementia (FTD).

We've created a yeast model, the same cells that bakers and brewers use to make bread and beer, to express TDP-43, explains lead author Aaron D. Gitler, PhD, Assistant Professor of Cell and Developmental Biology. Remarkably, this protein formed clumps in our simple yeast cells just like it does in human nerve cells. In our paper we determine which segments of the mutated TDP-43 protein cause it to aggregate and which parts cause it to be toxic. Gitler and colleagues report their findings in this weeks advance online issue of the Proceedings of the National Academy of Sciences.

Two years ago, other Penn investigators found that TDP-43 accumulated abnormally in post-mortem brain or nervous system tissue from individuals diagnosed with either ALS or FTD. TDP-43 is normally involved in RNA and DNA processing, among other cellular tasks. The recent TDP-43 mutation studies confirm the proteins role in causing disease.

The clumping process of proteins takes decades in humans but the researchers could model the process within a matter of hours in yeast cells. This now allows for rapid genetic screening to identify proteins that can reverse the harmful effects of the disease protein; visualizing the clumping; and testing molecules that could eliminate or prevent clumping.

Our yeast model will be a powerful tool for performing large-scale drug screens to look for small molecules that can prevent TDP-43 from aggregating or that can protect cells from aggregated TDP-43, notes Gitler.

Normally, TDP-43 sta
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert

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