Penn researchers find potential in yeast for selecting Lou Gehrig's disease drugsApril 18, 2008PHILADELPHIA - 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 week's 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 protein's 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 stays in the nucleus, but in ALS and FTD it somehow gets sequestered into the cell's cytoplasm, where it forms clumps. "When we put TDP-43 in yeast cells at normal human levels, it remained in the nucleus," explains Gitler. "However, when it was expressed at higher levels, thereby overwhelming the quality control systems of the cell, TDP-43 clumped in the cytoplasm. At even higher levels, TDP-43 became toxic to the yeast cells, making them unable to grow." This experiment suggests, for the first time, that TDP-43 clumps can be a direct cause of cell toxicity. In earlier studies at Penn, researchers found fragments of TDP-43 that were abundant in the clumps found in the post-mortem tissue of ALS and FTD patients. Knowing this, Gitler and colleagues chopped TDP-43 into many fragments to find the segments that are responsible for clumping and toxicity. They found a very similar segment that was also toxic to yeast cells. Designs of future drugs will depend on what part of the TDP-43 protein needs to be disabled. The researchers are able to overexpress every yeast gene to determine which genes can rescue the yeast cells from the TDP-43 toxicity. In addition to these genetic screens, Gitler and colleagues are pursuing drug screens with their TDP-43 model. "We can screen hundreds of thousands of small molecules to see which can get into a yeast cell and prevent TDP-43 from being toxic," says Gitler. "Then we can take the hits we find and test them in animal models. We have already made mutations identical to what have been found in patients and have introduced those in the yeast model." University of Pennsylvania School of Medicine |
|||||||||||||||||||||
| Related Yeast Cells Current Events and Yeast Cells News Articles Gerton Lab determines the composition of centromeric chromatin The Stowers Institute's Gerton Lab has provided new evidence to clarify the structure of nucleosomes containing Cse4, a centromere-specific histone protein required for proper kinetochore function, which plays a critical role in the process of mitosis. The work, conducted in yeast cells, was published in the most recent issue of Molecular Cell. Landmark study sheds new light on human chromosomal birth defects Using yeast genetics and a novel scheme to selectively remove a single protein from the cell division process called meiosis, a cell biologist at The Florida State University found that when a key molecular player known as Pds5 goes missing, chromosomes fail to segregate and pair up properly, and birth defects such as Down syndrome can result. UCSF researchers program cells to be remote-controlled by light UCSF researchers have genetically encoded mouse cells to respond to light, creating cells that can be trained to follow a light beam or stop on command like microscopic robots. RNA interference found in budding yeasts Some budding yeast species have the ability to silence genes using RNA interference (RNAi). Until now, most researchers thought that no budding yeasts possess the RNAi pathway because Saccharomyces cerevisiae, the protoypical model budding yeast does not. Mounting a multi-layered attack on fungal infections Unravelling a microbe's multilayer defence mechanisms could lead to effective new treatments for potentially lethal fungal infections in cancer patients and others whose natural immunity is weakened. New information about DNA repair mechanism could lead to better cancer drugs Researchers at Washington University School of Medicine in St. Louis have shed new light on a process that fixes breaks in the genetic material of the body's cells. Discovery of the cell's water gate may lead to new cancer drugs The flow of water into and out from the cell may play a crucial role in several types of cancer. Scientists at the University of Gothenburg have now found the gate that regulates the flow of water into yeast cells. Saved by junk DNA VIB researchers linked to K.U.Leuven and Harvard University show that stretches of DNA previously believed to be useless 'junk' DNA play a vital role in the evolution of our genome. Using high-precision laser tweezers to juggle cells Researchers at the University of Gothenburg, Sweden, have developed a new method to study single cells while exposing them to controlled environmental changes. Redefining what it means to be a prion Whitehead Institute researchers have quintupled the number of identifiable prion proteins in yeast and have further clarified the role prions play in the inheritance of both beneficial and detrimental traits. More Yeast Cells Current Events and Yeast Cells News Articles |
|||||||||||||||||||||
|
|||||||||||||||||||||
|
|||||||||||||||||||||