Navigation Links
St. Jude Children's Research Hospital scientists identify ALS disease mechanism
Date:8/28/2013

(MEMPHIS, Tenn. August 28, 2013) Researchers have tied mutations in a gene that causes amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders to the toxic buildup of certain proteins and related molecules in cells, including neurons. The research, published recently in the scientific journal Cell, offers a new approach for developing treatments against these devastating diseases.

Scientists at St. Jude Children's Research Hospital and the University of Colorado, Boulder, led the work.

The findings provide the first evidence that a gene named VCP plays a role in the break-up and clearance of protein and RNA molecules that accumulate in temporary structures called RNA granules. RNAs perform a variety of vital cell functions, including protein production. RNA granules support proper functioning of RNA.

In ALS and related degenerative diseases, the process of assembling and clearing RNA granules is impaired. The proteins and RNAs associated with the granules often build up in nerve cells of patients. This study shows how mutations in VCP might contribute to that process and neurodegenerative disease.

"The results go a long way to explaining the process that links a variety of neurodegenerative diseases, including ALS, frontotemporal dementia and related diseases of the brain, muscle and bone known as multisystem proteinopathies," said the study's co-corresponding author, J. Paul Taylor, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. Roy Parker, Ph.D., of the University of Colorado's Department of Chemistry and Biochemistry and the Howard Hughes Medical Institute (HHMI), is the other corresponding author.

ALS, also known as Lou Gehrig's disease, is diagnosed in about 5,600 Americans annually and is associated with progressive deterioration of nerve cells in the brain and spine that govern movement, including breathing. There is no effective treatment, and death usually occurs within five years.

"A strength of this study is that it provides a unifying hypothesis about how different genetic mutations all affect stress granules, which suggests that understanding stress granule dynamics and how they can be manipulated might be beneficial for treatment of these diseases," Parker said.

Earlier work from Taylor's laboratory identified mutations in VCP as a cause of ALS and related multisystem proteinopathies. Until now, however, little was known about how those mistakes caused disease. The latest findings appeared in the June 20 issue and are highlighted in a review article published in the August 15 issue of Cell.

The research also ties VCP mutations to disruption of RNA regulation, which prior studies have connected to the progression of neurodegenerative diseases, said Regina-Maria Kolaitis, Ph.D., a postdoctoral fellow in Taylor's laboratory. She and Ross Buchan, Ph.D., a postdoctoral fellow in Parker's laboratory, are co-first authors.

The work focused on a class of RNA granules called stress granules. They are formed by proteins and an RNA molecule called mRNA that accumulates in the cell cytoplasm in response to stress. Stressed cells do not want to waste energy producing unnecessary proteins. Stress granules are one mechanism cells use to halt production until the cellular environment normalizes, which is when stress granules typically dissolve.

Proteins found in stress granules include RNA-binding proteins like TDP-43, FUS, hnRNPA1 and hnRNPA2B1 that regulate gene activity. Mutations in those proteins can also cause ALS and related disorders.

"VCP has many functions in cells, but it is not an RNA-binding protein and until now it was not connected to stress granules or RNA processing," Kolaitis said. "This study provides a new window into the disease process, highlighting VCP's role in keeping cells healthy."

For this study, researchers used yeast to identify a network of 125 genes that affect the formation and behavior of stress granules. One of the genes that appeared to play a central role in the network was CDC48, which functions like VCP in yeast. In addition, many of the genes identified are involved in a process called autophagy that cells use to break down and recycle unneeded molecules, including proteins.

Working in yeast and mammalian cells, researchers showed that stress granules are cleared by autophagy, which stalled when VCP was mutated. Researchers also reported that stress granules accumulated following mutation of either CDC48 or VCP.

"This work suggests that activating autophagy to help rid cells of stress granules offers a new approach to neurodegenerative disease treatment," Taylor said.


'/>"/>

Contact: Carrie Strehlau
carrie.strehlau@stjude.org
901-595-2295
St. Jude Children's Research Hospital
Source:Eurekalert

Related medicine news :

1. UCLA Brain Injury Research Center gets NCAA funding for research on sports concussions
2. NIH awards $20 million over 5 years to train next generation of global health researchers
3. Researchers develop a new cell and animal model of inflammatory breast cancer
4. Researchers uncover a viable way for colorectal cancer patients to overcome drug resistance
5. Sexually abused boys at risk for more unsafe sex: UBC research
6. Researchers Find Gene Mutations That May Be a Key to Autism
7. LSUHSC research finds HPV-related head & neck cancers rising, highest in middle-aged white men
8. Researchers find evidence of banned antibiotics in poultry products
9. Presidential keynote address and new research highlights from the American Society of Pediatric Otolaryngology meeting
10. Scientific session and new research highlights
11. NJ stroke researchers report advances in spatial neglect research at AAN Conference
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/11/2016)... ... February 11, 2016 , ... Florida Hospital presents Heart Health Awareness night ... Louis Blues at the Amalie Arena. The puck drops at 6:00pm, but fans will ... MEGA Heart, prior to the game. The MEGA Heart will be located on Ford ...
(Date:2/11/2016)... ... February 11, 2016 , ... ... has been gearing up for their simultaneous grand openings in March. All seven ... now that you’re probably wondering, is reversing diabetes possible? According to this 2011 ...
(Date:2/11/2016)... Plantation, Fla. (PRWEB) , ... February 11, 2016 ... ... CareTRAK™, an unparalleled clinical decision support technology, with highly adaptable algorithms, has ... cases. When a patient has signs and symptoms consistent with Zikas and a ...
(Date:2/11/2016)... ... February 11, 2016 , ... Greenfield Insurance Group in ... to assist the people of their local community. The agency pledges to select ... leaders. Their hope is to bring awareness to important local causes with fundraising ...
(Date:2/11/2016)... ... February 11, 2016 , ... Dickinson Insurance & Financial Services continues their ... fundraiser in support of a local boy named Barrett, who has been fighting ALL ... to, and rally support for, all local families dealing with childhood cancer. Information on ...
Breaking Medicine News(10 mins):
(Date:2/11/2016)... --  Health 2.0 , the premiere showcase and catalyst ... " 10 Year Global Retrospective ", a platform to ... ten years.   --> ... served as the preeminent thought-leader in the health tech ... companies, innovators, and patient-activists through an array of events ...
(Date:2/11/2016)... , Feb. 11, 2016 AAIPharma ... provider of custom manufacturing and development services for ... sterile fill-finish capabilities and capacity in its ... in demand has driven several recent investments. ... it had one filling line with small-scale lyophilization. ...
(Date:2/11/2016)... ANKENY, Iowa , 11 de fevereiro de ... a inauguração de sua fábrica de soroalbumina bovina ... Nova Zelândia. A fábrica fica na Ilha Norte ... Loop "), desenvolvido e estabelecido na fábrica da ... Iowa . O projeto e instalação dos ...
Breaking Medicine Technology: