Scientists at the Scripps Research Institute have found a DNA twist to schizophrenia - the DNA staying too tightly wound in certain brain cells could be causing the disease.
The research, now available online in the new Nature journal, Translational Psychiatry, shows the deficit is especially pronounced in younger people, meaning treatment might be most effective early on at minimizing or even reversing symptoms of schizophrenia.
Advertisement"We're excited by the findings," said Scripps Research Associate Professor Elizabeth Thomas, a neuroscientist who led the study, "and there's a tie to other drug development work, which could mean a faster track to clinical trials to exploit what we've found."
"There's so much DNA in each cell of your body that it could never fit in your cells unless it was tightly and efficiently packed," said Thomas. Histone "tails" regularly undergo chemical modifications to either relax the DNA or repack it. When histones are acetylated, portions of DNA are exposed so that the genes can be used. The histone-DNA complexes, known as chromatin, are constantly relaxing and condensing to expose different genes, so there is no single right or wrong configuration. But the balance can shift in ways that can cause or exacerbate disease.
DNA is the guide that cellular machinery uses to construct the countless proteins essential to life. If portions of that guide remain closed when they shouldn't because histones are not acetylated properly, then genes can be effectively turned off when they shouldn't be with any number of detrimental effects. Numerous research groups have found that altered acetylation may be a key factor in other conditions, from neurodegenerative disorders such as Huntington's disease and Parkinson's disease to drug addiction.
Working with lead author Bin Tang, a postdoctoral fellow in her lab, and Brian Dean, an Australian colleague at the University of Melbourne, Thomas obtained post-mortem brain samples from schizophrenic and healthy brains held at medical "Brain Banks" in the United States and Australia.
Compared to healthy brains, the brain samples from subjects with schizophrenia showed lower levels of acetylation in certain histone portions that would block gene expression. Another critical finding was that in younger subjects with schizophrenia, the problem was much more pronounced.
Just what causes the acetylation defects among schizophrenic subjects—what keeps certain pages of the DNA guide closed—isn't clear, but from a medical perspective it doesn't matter. If researchers can reliably show that acetylation is a cause of the problem, they can look for ways to open the closed guide pages and hopefully cure or improve the condition in patients.
Thomas sees great potential. Based on the more pronounced results in younger brains, she believes that treatment with histone deacetylase inhibitors might well prove helpful in reversing or preventing the progression of the condition, especially in younger patients. Current drugs for schizophrenia tend to treat only certain symptoms, such as hallucinations and delusions, and the drugs have major side effects including movement problems, weight gain, and diabetes. If deacetylase inhibitors effectively treat a root cause of the disease and prove sufficiently non-toxic, they might improve additional symptoms and provide a major expansion of treatment options.
Interestingly, some of the cognitive deficits that plague elderly people look quite similar biologically to schizophrenia, and the two conditions share at least some brain abnormalities. So deacetylase inhibitors might also work as a treatment for age-related problems, and might even prove an effective preventive measure for people at high risk of cognitive decline based on family history or other indicators.
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