Navigation Links
Yeast model offers clues to possible drug targets for Lou Gehrig's disease, study shows
Date:10/28/2012

STANFORD, Calif. Amyotrophic lateral sclerosis, also called Lou Gehrig's disease, is a devastatingly cruel neurodegenerative disorder that robs sufferers of the ability to move, speak and, finally, breathe. Now researchers at the Stanford University School of Medicine and San Francisco's Gladstone Institutes have used baker's yeast a tiny, one-celled organism to identify a chink in the armor of the currently incurable disease that may eventually lead to new therapies for human patients.

"Even though yeast and humans are separated by a billion years of evolution, we were able to use the power of yeast genetics to identify an unexpected potential drug target for ALS," said Aaron Gitler, PhD, an associate professor of genetics at Stanford. "Many neurodegenerative disorders such as ALS, Parkinson's and Alzheimer's exhibit protein clumping or misfolding within the neurons that is thought to either cause or contribute to the conditions. We are trying to figure out why these proteins aggregate in neurons in the brain and spinal cord, and what happens when they do."

In 2008, Gitler received a New Innovator award from the National Institutes of Health to use yeast as a model for understanding human neurodegenerative diseases and as a way to identify new targets for drug development.

Gitler is the co-senior author of the research, which will be published online Oct. 28 in Nature Genetics. Robert Farese, Jr., MD, a senior investigator at the Gladstone Institutes, is the other co-senior author. Stanford graduate student Maria Armakola shares co-first authorship with Matthew Higgins, PhD, a postdoctoral scholar at Gladstone.

Most cases of ALS have no clear-cut cause. However, it has recently been shown that an RNA-binding protein called TDP-43 accumulates in clumps in the cytoplasm of spinal cord neurons in many people with the condition, and mutations in this protein have been found in some people with the ALS. Researchers like Gitler and Farese have been able to mimic the disease in yeast by expressing TDP-43 at higher-than-normal levels, which causes the protein to form lethal clumps in the cells' cytoplasm.

"In humans, the progression of the disease can take years before symptoms arise," said Gitler. "But in yeast, we see protein clumping in the cytoplasm within two days and the cells rapidly begin to die." With their model system in place, Gitler and Farese set out to see whether it was possible to protect yeast cells from this effect by tinkering with the function of other proteins in the cell.

In this study, the researchers discovered that blocking the production of a protein called Dbr1 in a yeast model stops the TDP-43 clumping and allows the cells to live normally. The researchers confirmed the results in human nerve cells grown in the laboratory and in rat neurons overexpressing TDP-43.

"In this study we made no assumptions as to how TDP-43 injures cells," said Farese, "but instead screened the whole yeast genome to find genes that might prevent the toxicity. Independently, both our lab and the Gitler lab found that loss of Dbr1, an enzyme involved in RNA processing, could do this."

Dbr1 serves as part of the cellular clean-up crew that mops up the bits of unwanted RNA generated as part of the protein production line. In our DNA, most genes consist of coding regions, called exons, broken up into several segments by non-coding regions, called introns. Cells can make many different, related proteins from the same stretch of DNA by mixing and matching different exons in a process called splicing.

When the DNA is first copied, or transcribed, into RNA, the introns as well as the exons are included. But the cell quickly splices out the introns, which are released into the cytoplasm as little loops, or lariats. Dbr1, in turn, clips the loops to open them and make them accessible to the cell's disposal system.

Blocking the production of Dbr1 causes the RNA lariats to build up in the cytoplasm. The researchers showed by creating lariats with a binding site for a fluorescent tracking protein that the mutant TDP-43 binds to these excess lariats rather than clumping. The effect is like using a paper towel to mop up a spill on your computer keyboard: binding to the lariats appears to keep TDP-43 from causing havoc elsewhere.

"Normally, TDP-43 is found in the nucleus," said first author Armakola. "But in the diseased cells, it aggregates in the cytoplasm and forms clumps. We developed a novel way to track where these lariats go in living cells, and we saw that when Dbr1 is missing, the lariats act as a sink to sequester TDP-43."

The researchers note that it's still not entirely clear whether the cells die because the mutant TDP-43 is drawing essential RNA transcripts or regulatory molecules away from the nucleus and into the cytoplasm, or because it's not performing its normal RNA-binding function in the nucleus. Both could contribute to the progression of the disease.

The results in the yeast, rodent and human cells, however, suggest that therapeutic approaches aimed at blocking Dbr1 function, or even creating artificial lariat-like formations to draw away the mutant molecule, should be explored.

"Next, we'd like to explore blocking Dbr1 function in animals such as flies, worms and rodents," said Armakola. "We're also interested in identifying small molecule inhibitors of Dbr1."


'/>"/>
Contact: Krista Conger
kristac@stanford.edu
650-725-5371
Stanford University Medical Center
Source:Eurekalert

Related medicine news :

1. Models developed from the PLCO may help identify at-risk patients for adverse smoking outcomes
2. Drug shows promise in animal model of Alzheimers and Parkinsons with dementia
3. Mouse model exposes a new type of T cell to target melanoma
4. Modeling Good Research Practices guidelines for modeling in health care research available now
5. Genetically-engineered preclinical models predict pharmacodynamic response
6. Weizmann Institutes mathematical model may lead to safer chemotherapy
7. Modeling sepsis in newborns
8. A model for development
9. A CNIO team creates a unique mouse model for the study of aplastic anaemia
10. A new model for predicting recovery after spinal cord injury
11. TRPM7 protein key to breast cancer metastasis in animal models
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/30/2017)... Viejo, CA (PRWEB) , ... April 30, 2017 ... ... animations created exclusively for use in Final Cut Pro X. Editors can pick ... and more. Easily change the highlights, mid levels and shadows using simple color ...
(Date:4/29/2017)... ... April 29, 2017 , ... TransDark is a set of ... video to the next without having to set a single keyframe in Final ... enhance your video production. , TransDark features dynamic transitions that momentarily splits the RGB ...
(Date:4/28/2017)... ... April 28, 2017 , ... An April 24th article on Yahoo! Beauty ... pounds with the help of a weight loss surgery. The woman, declaring “I will not ... have been left following her dramatic weight loss. Dr. Feiz & Associates notes that, while ...
(Date:4/28/2017)... ... , ... Beginning in 2017, Ridgecrest Herbals will be phasing out the homeopathic ... Extra Strength formula. To ensure that the effectiveness of Clear Lungs Extra Strength is ... , Removal of the homeopathic element , Adding their patented ...
(Date:4/28/2017)... ... April 28, 2017 , ... Ushio America proudly introduces ... an instant energy-saving solution for F32T8 fluorescent lamps on most instant-start and programmed-start ... 50,000 hour rated lamps utilize the existing electronic ballast, saving labor and maintenance ...
Breaking Medicine News(10 mins):
(Date:4/20/2017)... , April 20, 2017   ZappRx, Inc ., ... specialty drug prescribing process, today announced it closed $25 million ... a venture capital firm based in Seattle ... Qiming Venture Partners . The Series B round included participation ... round in 2014, and GV (formerly Google Ventures). ...
(Date:4/20/2017)... Research and Markets has announced the addition of ... By Service (Manufacturing, Research), By Country, (Brazil, Mexico, Colombia, Argentina, ... to their offering. ... The Latin American pharmaceutical contract manufacturing services market is anticipated ... drug registration cost in Latin American countries and continuous economic ...
(Date:4/19/2017)... , April 19, 2017 Global Surgical Drainage ... are tubes used to remove excess liquid and air. ... pus, urine, bile or lymph. Surgical drains are used ... such as orthopedics surgery, cardiovascular surgery, neurosurgery, plastic surgery ... post-surgery to prevent accumulation of fluid e.g. blood or ...
Breaking Medicine Technology: