(Press-News.org) A molecular pathway known to suppress tumors appears to also be a major player in clearing cells of damaged proteins implicated in neurodegenerative diseases such as ALS and certain types of dementia, new research in roundworms and human cells suggests.
Johns Hopkins Bloomberg School of Public Health researchers, publishing April 2 in the journal PLOS Biology, say their findings shed new light on how a cell's protein quality control mechanism works - and how this system could be harnessed one day to combat diseases caused by a buildup of proteins in cells. To function properly, proteins must assume their correct three-dimensional shape, a process known as protein folding. Researchers have long known that too many misfolded proteins are associated with neurotoxicity.
"In healthy cells, there is a normal process that gets rid of damaged proteins or repairs them. If that balance is perturbed, the cell will be faced with the accumulation of misfolded proteins that can lead to disease," says study leader Jiou Wang, MD, PhD, an assistant professor in the Department of Biochemistry and Molecular Biology at the Johns Hopkins Bloomberg School of Public Health and in the Department of Neuroscience at the Johns Hopkins University School of Medicine. "We think our discovery is potentially important because it contributes to our understanding of what we might be able to change in a cell to defend against the burden of misfolded proteins. If this can be extended to humans, it might have a therapeutic value."
Wang and his team began their research in Caenorhabditis elegans, a type of roundworm. Researchers study roundworm because its simple central nervous system enables them to analyze, in a shortened time frame, how tens of thousands of different genes behave. They took a gene that encodes for ALS, also known as Lou Gehrig's disease, a debilitating condition that attacks the brain and nerve cells responsible for motion, and inserted it into the roundworm into those neurons.
As expected, the gene caused the misfolding of proteins in the roundworms' neurons and the ability of the neurons to control movement was greatly reduced. Then the researchers randomly inactivated other genes in the roundworms, and then tested their ability to improve their movement. In a rare few instances, the roundworms' mobility actually improved. This led the researchers to determine that when two genes - ufd-2 and spr-5 - were turned off, there were fewer misfolded proteins, thereby reducing their detrimental impact on movement.
The researchers repeated their work in human cells, finding the same results when the human versions of ufd-2 and spr-5 were switched off. The researchers were then able to determine that p53 - a well-studied tumor suppression gene - was involved in regulating when the two identified genes (in humans, known as UBE4B and LSD1) were turned up and when they were turned down. The pathway mediated by p53 is known to be involved in how cells respond to DNA damage and it appears to move into action when a large number of damaged proteins are present.
"Our research tells us there may be one master switch controlling both DNA damage and protein damage," says study co-author Goran Periz, PhD, a senior postdoctoral fellow working with Wang at the Bloomberg School. "When p53 is involved, it acts as part of a quality control mechanism and helps activate the removal of misfolded proteins from cells before they can cause permanent damage."
In the future, the findings could help researchers find a way to treat neurodegenerative diseases for which there is no cure, Wang says.
"Now we want to know what changes can we make to cells to improve the situation," he says.
INFORMATION:
"Regulation of Protein Quality Control by UBE4B and LSD1 through p53-Mediated Transcription" was written by Goran Periz; Jiayin Lu; Tao Zhang; Mark W. Kankel; Angela M. Jablonski; Robert Kalb; Alexander McCampbell; and Jiou Wang.
This work was supported by grants from the National Institutes of Health's National Institute of Neurological Disorders and Stroke (NS074324 and NS062089); the U.S. Department of Defense (W81XWH-12-1-0570), the Robert Packard Center for ALS Research at Johns Hopkins and the JHU-Biogen IDEC consortium.
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