Newly identified mechanism solves enduring mystery of key element of cellular organization

September 24, 2015, St. Jude Children's Research Hospital
St. Jude scientists (from left are) Tanja Mittag, Ph.D., an assistant member of the Department of Structural Biology; Amandine Palud, student; and J. Paul Taylor, M.D., Ph.D., a Howard Hughes Medical Institute investigator and chair of the Department of Cell and Molecular Biology. Credit: St. Jude Children's Research Hospital

St. Jude Children's Research Hospital scientists have discovered evidence of a mechanism at the heart of amyotrophic lateral sclerosis (ALS) and related degenerative diseases. The research appears in today's edition of the journal Cell and highlights a possible new treatment strategy for the devastating disorders.

The study focused on usually short-lived compartments called stress granules that form in cells under stress. Stress granules are just one type of the membrane-less structures or organelles that assemble as needed to handle various cell functions and then rapidly disperse. Until now, however, the mechanism underlying stress granule formation was poorly understood.

Stress granules are also tied to degenerative disorders such as ALS, which is also known as Lou Gehrig's disease. Genes encoding the protein components of stress granules are often mutated in patients with ALS and other diseases. These same proteins accumulate in thread-like deposits called amyloid fibrils in the nerve and muscle cells of patients with ALS, frontotemporal dementia (FTD) and inclusion body myopathy (IBM). But the unifying mechanism was a mystery.

"This study provides the mechanism that links stress granules, toxic fibrils and disease," said co-corresponding author J. Paul Taylor, M.D., Ph.D., a Howard Hughes Medical Institute (HHMI) investigator and chair of the St. Jude Department of Cell and Molecular Biology. "In addition to advancing our understanding of fundamental cell biology, the results have spurred interest in developing drugs that target the stress granule assembly process."

The disordered segment or "tail" of hnRNPA1, a protein that is sometimes mutated in ALS and related disorders, was the key to unlocking the connection among stress granules, fibrils and disease, said co-corresponding author Tanja Mittag, Ph.D., an assistant member of the St. Jude Department of Structural Biology. hnRNPA1 is an RNA-binding protein involved in stress granule formation.

Proteins are long strings of amino acids that usually fold into specific 3-D structures. hnRNPA1 belongs to a subset of proteins with an amino acid arrangement that prevents folding of one end of the protein, which allows hnRNPA1 to adopt a variety of conformations.

In this study, researchers showed that under certain conditions related to temperature, salt and protein concentrations, hnRNPA1's disordered tail prompts the protein to condense into liquid droplets through a process called liquid . The droplets have properties similar to stress granules, including the ability to fuse and grow.

Liquid phase separation is at work in a wide range of settings, including when oil and vinegar separate in salad dressing. Until recently, however, the process was not believed to play a role in normal cell function. This study is the first to link liquid phase separation to stress granule assembly.

"It is amazing to find out that proteins like hnRNPA1 have appeared in nature to mediate liquid phase separation under normal physiological conditions," Mittag said. "The long disordered tails in these proteins enable membrane-less compartmentalization in cells. In addition, liquid phase separation is probably important for a whole range of fundamental biological processes."

Working in the laboratory, researchers also showed how the mutations likely contribute to disease. When hnRNPA1 with mutations in the disordered tail underwent separation and concentrated into droplets, the protein almost immediately formed amyloid-like fibrils. If the mutant protein did not concentrate into droplets, however, toxic fibrils did not form.

The finding also suggests how mutations in genes like VCP promote disease. Previous research from Taylor and his colleagues have linked mutations in the gene to ALS and related disorders. VCP plays a role in dismantling stress granules when they are no longer needed. By allowing to persist, this study suggests that VCP mutations increase the likelihood that amyloid-like fibrils will form and spread.

"Rather than attempting to target each disease-causing mutation, these findings have generated interest in developing drugs that target the stress granule assembly process," Taylor said.

Currently there are no effective therapies for ALS, FTD or IBM, which are associated with a variety of neurological changes as well as muscle weakness and paralysis that affects walking, swallowing and breathing. Government agencies and advocacy groups estimate that 30,000 U.S. residents have ALS and that FTD accounts for about 10 percent of the 5.3 million Americans with dementia. IBM is one of several related disorders that, combined, affects about 50,000 residents.

Explore further: Scientists identify ALS disease mechanism

Related Stories

Scientists identify ALS disease mechanism

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 ...

Two new genes linked to amyotrophic lateral sclerosis and related disorders

March 18, 2013
(Medical Xpress)—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, ...

Silent RNAs express themselves in ALS disease

December 2, 2013
RNA molecules, used by cells to make proteins, are generally thought to be "silent" when stowed in cytoplasmic granules. But a protein mutated in some ALS patients forms granules that permit translation of stored RNAs, according ...

Stress granules ease the way for cancer metastasis

March 23, 2015
Tumors that produce more stress granules are more likely to metastasize, according to a study published in The Journal of Cell Biology. The results suggest that drugs to inhibit the formation of these structures might rein ...

Proteins with mutations in 'prion-like' segments considered candidates for inherited forms of ALS

March 3, 2013
A multi-institution group of researchers has found new candidate disease proteins for neurodegenerative disorders. James Shorter, Ph.D., assistant professor of Biochemistry and Biophysics at the Perelman School of Medicine, ...

Researchers reveal how a common mutation causes neurodegenerative disease

August 26, 2015
Researchers have determined how the most common gene mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) disrupts normal cell function, providing insight likely to advance efforts to develop ...

Recommended for you

3-D bioPen: A hydrogel injection to regenerate cartilage

September 25, 2018
Highly specialized cartilage is characteristically avascular and non-neural in composition with low cell numbers in an aliphatic environment. Despite its apparent simplicity, bioengineering regenerative hyaline cartilage ...

Skin wounds in older mice are less likely to scar

September 25, 2018
Researchers have discovered a rare example in which the mammalian body functions better in old age. A team at the University of Pennsylvania found that, in skin wounds in mice, being older increased tissue regeneration and ...

Study finds that enzymes 'partner up' to accelerate cancer, aging diseases

September 25, 2018
A new study from molecular biologists at Indiana University has identified cellular processes that appear to supercharge both the growth and shrinkage of the chemical "caps" on chromosomes associated with aging, called telomeres.

Extracellular RNA in urine may provide useful biomarkers for muscular dystrophy

September 25, 2018
Massachusetts General Hospital (MGH) researchers have found that extracellular RNA (exRNA) in urine may be a source of biomarkers for the two most common forms of muscular dystrophy, noninvasively providing information about ...

Evidence that addictive behaviors have strong links with ancient retroviral infection

September 24, 2018
New research from an international team led by Oxford University's Department of Zoology and the National-Kapodistrian University of Athens, published today in Proceedings of the National Academy of Sciences (PNAS), shows ...

Taking a catnap? Mouse mutation shown to increase need for sleep

September 24, 2018
Sleep is vital for adequate functioning across the animal kingdom, but little is known about the physiological mechanisms that regulate it, or the reasons for natural variation in people's sleep patterns.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.