Researchers at Rutgers University studying the cause of a rare childhood disease that leaves children unable to walk by adolescence say new findings may provide clues to understanding more common neurodegenerative diseases like Alzheimer's and Parkinson's. They add that this knowledge might lead to the development of new ways to treat these disorders.
The scientists published details on their work in a paper (“EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia”) that appears online in the current edition of Nature Neuroscience. They focused on ataxia-telangiectasia (A-T disease), a rare genetic childhood disorder that occurs in an estimated one in 40,000 births.
“The symptoms of [A-T] include a progressive neurodegeneration caused by ATM protein deficiency,” they wrote. “We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased trimethylation of histone H3 on Lys27 (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) is also important in the A-T phenotype.”
Children born with A-T disease have mutations in both of their copies of the ATM gene and cannot make normal ATM protein. This leads to problems in movement, coordination, equilibrium, and muscle control as well as a number of other deficiencies outside the nervous system.
Using mouse and human brain tissue studies, Rutgers researchers found that without ATM, the levels of a regulatory protein known as EZH2 go up. Looking through the characteristics of A-T disease in cells in tissue culture and in brain samples from both humans and mice with ATM mutation, they found that the increase in EZH2 was a major contributing factor to the neuromuscular problems caused by A-T.
“We hope that this work will lead to new therapies to prevent symptoms in those with A-T disease,” explains Ronald Hart, Ph.D., in the department of cell biology and neuroscience. “But on a larger level, this research provides a strong clue toward understanding more common neurodegenerative disorders that may use similar pathways. It is a theme that has not yet been examined.”
While the EZH2 protein has been shown to help determine whether genes get turned on or off, altering the body's ability to perform biological functions necessary for maintaining good health, the Rutgers study is the first time this protein, which can cause adverse health effects if there is too much of it, has been looked at in the mature nerve cells of the brain.
By reducing the excess EZH2 protein that accumulated in mice genetically engineered with A-T disease, and creating a better protein balance within the nerve cells, Rutgers scientists found that mice exhibited improved muscle control, movement, and coordination.
The hope is that this new information can be used to develop therapeutic drugs that may result in better neuromuscular control and coordination for those with A-T disease. In addition, the scientists will work to determine whether the EZH2 protein plays a role in other more common neurodegenerative diseases like Parkinson's and Alzheimer's and could offer a target for developing drugs to treat those brain disorders.