Navigation Links
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 stays in the nucleus, but in ALS and FTD it somehow gets sequestered into the cells 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.


'/>"/>

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

Related medicine news :

1. MU researchers find clue to cataract formation
2. Researchers evaluating food allergy treatment
3. U of M researchers identify process that may help treat Parkinsons, spinal cord injuries
4. OHSU Cancer Institute researchers discover key gene involvement in cancer development
5. Combining liver cancer treatments doubles survival rates, UVA researchers find
6. Leading HIV researchers to collaborate on vaccine development
7. Georgetown researchers find stem cell marker controls 2 key cancer pathways
8. Blood pressure drugs halt pancreatic cancer cell growth, Jefferson researchers find
9. OHSU Cancer Institute researchers find connection between protein, prognosis in breast cancer
10. Karmanos Researchers Report Enhanced Chemosensitivity of Pancreatic Cancer Cells by Black Seed Component
11. Penn researchers find targeted therapy combination overcomes treatment resistance in liver cancer
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/24/2016)... ... June 24, 2016 , ... June 19, 2016 is ... associated with chronic pain and the benefits of holistic treatments, Serenity Recovery Center ... suffering with Sickle Cell Disease. , Sickle Cell Disease (SCD) is a disorder of ...
(Date:6/24/2016)... ... 24, 2016 , ... The Pulmonary Hypertension Association (PHA) learned ... receive two significant new grants to support its work to advance research and ... by recognizing patients, medical professionals and scientists for their work in fighting pulmonary ...
(Date:6/24/2016)... ... June 24, 2016 , ... Dr. Amanda Cheng, an ... Cheng has extensive experience with all areas of orthodontics, including robotic Suresmile technology, ... , Micro-osteoperforation is a revolutionary adjunct to orthodontic treatment. It can be ...
(Date:6/24/2016)... ... ... makers of Topricin and MyPainAway Pain Relief Products, join The ‘Business for a Fair Minimum ... by 2020 and then adjusting it yearly to increase at the same rate as the ... wage floor does not erode again, and make future increases more predictable. , The company ...
(Date:6/24/2016)... ... June 24, 2016 , ... EB Medicine presented its ... Emergency Medicine conference in Ponte Vedra Beach, FL. The awards honor the outstanding ... Medicine Practice and Pediatric Emergency Medicine Practice. , “With this award, we ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... June 24, 2016  Collagen Matrix, Inc., ("Collagen ... and manufacturing of collagen and mineral based medical ... that Bill Messer has joined the ... further leverage the growing portfolio of oral surgery, ... Bill joins the Collagen Matrix executive team ...
(Date:6/24/2016)... 24, 2016   Bay Area Lyme Foundation ... Dean Center for Tick Borne Illness , Harvard ... MIT Hacking Medicine, University of California, Berkeley, and ... the five finalists of Lyme Innovation , ... than 100 scientists, clinicians, researchers, entrepreneurs, and investors ...
(Date:6/24/2016)... -- Research and Markets has announced ... Applications, Technologies, Forecasts" report to their offering. ... Smart Skin, Structural Health Monitoring, Composite Smart Structures, ... involves electronic and/or electrical components and circuits that ... such as vehicle bodies or conformally placed upon ...
Breaking Medicine Technology: