Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

2 new genes linked to amyotrophic lateral sclerosis and related disorders

04.03.2013
St. Jude Children's Research Hospital ties mutations in 2 genes to the death of motor neurons associated with ALS, or Lou Gehrig's disease, and other devastating neurodegenerative problems

A study led by St. Jude Children's Research Hospital has discovered mutations in two genes that lead to the death of nerve cells in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, and related degenerative diseases.

The same mutation occurred in both genes and led to the abnormal build-up of the proteins inside cells. These proteins play an essential role in normal RNA functioning and have also been linked to cancer, including the Ewing sarcoma, the second most common type of bone cancer in children and adolescents. The finding is the latest in a series of discoveries suggesting degenerative diseases and cancer may have common origins. RNA is the molecule that directs protein assembly based on instructions carried in DNA.

The study also adds to evidence that seemingly unrelated neurodegenerative diseases may involve similar defects in RNA metabolism. Researchers linked the problems to a specific region of the mutated proteins whose normal function was unclear. The study was published today in the advanced online edition of the scientific journal Nature.

"I hope this study helps to build the foundation for desperately needed treatments for ALS and perhaps a broad range of diseases caused by abnormal RNA metabolism," said J. Paul Taylor, M.D., Ph.D., an associate member of the St. Jude Department of Developmental Neurobiology and senior author of the study. Taylor and James Shorter, Ph.D., an assistant professor in the biochemistry and biophysics department at the University of Pennsylvania's Perelman School of Medicine, are the study's corresponding authors.

Each year approximately 5,600 people in the U.S. are found to have ALS. The disease is nearly always fatal, often within five years. Patients suffer muscle wasting and paralysis that affects their limbs and trunk as well as their ability to talk, swallow and breathe. There is no cure.

For this project, St. Jude sequenced just the portion of the genome called the exome, which carries instructions for making proteins. Researchers sequenced the exomes of two families affected by rare inherited degenerative disorders that target cells in the muscle, bone and brain. Neither family carried mutations previously tied to ALS or related diseases. The project built on the infrastructure developed by the St. Jude Children's Research Hospital -- Washington University Pediatric Cancer Genome Project, which played an important role in finding the mutations.

Researchers found the families carried a single, previously unknown mutation in a pair of RNA-binding proteins named hnRNPA2B1 and hnRNPA1. The proteins both bind RNA and help regulate its function. When researchers checked for the same mutations in 517 ALS patients they found hnRNPA1 protein mutated in two patients. One patient had the inherited form of ALS. The other ALS patient had no family history of the disease.

The new mutations occurred in a region of the proteins Taylor refers to as a prion-like domain because it has similarities with yeast proteins called prions. Prions are proteins that can alternate between shapes as needed for different functions. "Until recently we did not know these domains existed in humans and now we realize that hundreds of human proteins have them," Taylor said. "We're only beginning to understand their function in human cells."

Researchers showed the prion-like domains are responsible for the shape change that occurs when these proteins convert into slender threads called fibrils. The mutations accelerate fibril formation and recruit normal proteins to form fibrils. This phenomenon called propagation may explain how ALS and related diseases spread throughout the nervous system.

Taylor speculated that the normal function of prion-like domains is to assemble RNAs into temporary structures called granules, which are part of the cell's normal protein production machinery. Granules are normally short lived, and the RNA-binding proteins involved in their formation are recycled. But in cells with hnRNPA2B1 or hnRNPA1 mutation, RNA granules accumulated in the cytoplasm instead of being disassembled. "That's bad news for RNA regulation, which is bad news for those cells," Taylor said.

The study has several important implications, Taylor said. Recognition that the mutations adversely impact regulation of RNA could lead to targeted therapy to correct the problem. The mutation's location in the prion-like domain might also prove significant. Although the mutations in hnRNPA2B1 or hnRNPA1 appear to be rare, hundreds of other RNA-binding proteins have prion-like domains. Taylor said patients with unexplained neurodegenerative diseases may have mutations in these proteins.

The study's first authors are Hong Joo Kim, Nam Chul Kim, Yong-Dong Wang and Jennifer Moore, all of St. Jude; and Emily Scarborough and Zamia Diaz, both of the University of Pennsylvania. The other authors are Kyle MacLea and Eric Ross, both of Colorado State University; Brian Freibaum, Songqing Li, Anderson Kanagaraj and Robert Carter, all of St. Jude; Amandine Molliex, formerly of St. Jude; Kevin Boylan, Aleksandra Wojtas and Rosa Rademakers, all of the Mayo Clinic, Jacksonville, Fla.; Jack Pinkus and Steven Greenberg, both of Brigham and Women's Hospital and Harvard Medical School; John Trojanowski, Bradley Smith, Yun Li and Alice Flynn Ford, all of the University of Pennsylvania; Bryan Traynor, of the National Institute of Aging, National Institutes of Health, Bethesda, Md.; Simon Topp, Athina-Soragia Gkazi, Jack Miller and Christopher Shaw, all of the Institute of Psychiatry, London; Michael Kottlors and Janbernd Kirschner, both of University Children's Hospital Freiburg, Germany; Alan Pestronk and Conrad Weihl, both of the Washington University School of Medicine, St. Louis; Aaron Gitler, Stanford University School of Medicine; Michael Benatar, University of Miami Miller School of Medicine; Oliver King, Boston Biomedical Research Institute, Watertown, Mass.; and Virginia Kimonis, University of California-Irvine.

The research was supported in part by the Packard Foundation, by grants (NS053825, AG032953, DP2OD002177 and NS067354) from the National Institutes of Health, the ALS Association, the Ellison Medical Foundation, a grant (MCB-1023771) from the National Science Foundation and ALSAC.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering research and treatment of children with cancer and other life-threatening diseases. The hospital's research has helped push overall survival rates for childhood cancer from less than 20 percent when the institution opened to almost 80 percent today. It is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, and no family ever pays St. Jude for anything. For more information, visit www.stjude.org. Follow us on Twitter @StJudeResearch.

Summer Freeman | EurekAlert!
Further information:
http://www.stjude.org

More articles from Life Sciences:

nachricht Scientists discover species of dolphin that existed along South Carolina coast
24.08.2017 | New York Institute of Technology

nachricht The science of fluoride flipping
24.08.2017 | University of North Carolina Health Care

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Scientists discover species of dolphin that existed along South Carolina coast

24.08.2017 | Life Sciences

The science of fluoride flipping

24.08.2017 | Life Sciences

Optimizing therapy planning for cancers of the liver

24.08.2017 | Medical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>