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:2/24/2017)... ... February 24, 2017 , ... The California State University Institute for Palliative ... in or interested in palliative care education and research. The Symposium, “Innovate. Investigate. ... County San Diego on Sept. 28 and 29, 2017, on the campus of California ...
(Date:2/24/2017)... ... February 24, 2017 , ... Rosica Communications, a national ... leadership , media relations, social media, content marketing and SEO, is now offering ... Act-On, an intuitive marketing automation platform. , Rosica will now offer the platform ...
(Date:2/23/2017)... Boulder, CO (PRWEB) , ... February 23, 2017 , ... ... to announce the winner of the 2016 National Education Policy Center Bunkum Award. We ... report reviewed in 2016. , This year’s Bunkum winner is the Center for American ...
(Date:2/23/2017)... , ... February 23, 2017 , ... Hamlin Dental Group ... that they are sponsoring a raffle. Throughout the month of February, patients who visit ... a gift card for a dinner for two at the Cheesecake Factory. , ...
(Date:2/23/2017)... ... February 23, 2017 , ... Pink ... publication where generations converge and explore the world from different perspectives. By providing ... enables readers to gain understanding, increase empathy, and find greater happiness. , ...
Breaking Medicine News(10 mins):
(Date:2/23/2017)... 2017  Genesis Healthcare Services has merged with Hospice ... by Bill Monast , President and CEO of ... Nathan Feltman , executives with Home Health Depot, Inc., ... This acquisition helps Hospice Cloud maintain its ... durable medical equipment (DME) solutions for the hospice industry. ...
(Date:2/23/2017)... Limited, ( ASX: ITD ), an innovative diversified healthcare company, is ... December 2016 compared with the previous corresponding period. A full "Results ... . Highlights Profit after ... Earnings per share of 2.2 cents (Dec 2015: 1.2 cents; up ... 11%) Profit before tax of $2.12m (Dec 2015: ...
(Date:2/23/2017)... 23. Februar 2017 Im Rahmen seiner ... Wirtschaftszone in der südwestlichen chinesischen Provinz Guizhou, 2017 mit dem ... Innovationsplattform aktiv an der Entwicklung einer eingebetteten Hightech-Schlüsselindustrie. ... Continue Reading ... ...
Breaking Medicine Technology: