Are schizophrenia sufferers 'too tightly wound' genetically?

Scripps Research scientists discover a brain cell malfunction in schizophrenia in effort that could help lead the way toward new therapies

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LA JOLLA, Calif.—Researchers at The ScrippsResearch Institute recently reported that their work has uncovered evidence that DNA stays "too tightly wound" in certain braincells of schizophrenic subjects. They say these findings suggest that drugs already indevelopment for other diseases might eventually offer hope as a treatment forschizophrenia and related conditions in the elderly.
The research, published in the journal Translational Psychiatry as the article "Disease- and age-related changes in histoneacetylation at gene promoters in psychiatric disorders," reportedly shows that the deficit is especiallypronounced in younger people, meaning treatment might be most effective earlyon at minimizing or even reversing symptoms of schizophrenia, which include hallucinations, delusions andemotional difficulties, among other problems.  
"We're excited by the findings," said Scripps Research associate professor Elizabeth Thomas, a neuroscientist who led the study, "andthere's a tie to other drug development work, which could mean a faster trackto clinical trials to exploit what we've found."
Epigenetics is a big factor in this research, and one critical area of epigenetic research, Scripps notes, is tied to histones, the structural proteins that DNA has to wrap around.
"There's so muchDNA in each cell of your body that it could never fit in your cells unless itwas tightly and efficiently packed," noted Thomas. Histone "tails" regularlyundergo chemical modifications to either relax the DNA or repack it. Whenhistones are acetylated, portions of DNA are exposed so that the genes can beused. The histone-DNA complexes, known as chromatin, are constantly relaxingand condensing to expose different genes, so there is no single right or wrongconfiguration. But the balance can shift in ways that can cause or exacerbatedisease.
DNA is the guide that cellular machinery uses to constructthe countless proteins essential to life, Scripps points out, so if portions of that guide remainclosed when they shouldn't because histones are not acetylated properly, thengenes can be effectively turned off when they shouldn't be and thereby bring about detrimental effects. Researchers on other projects worldwide have noted often that altered acetylationmay be a key factor in other conditions, from neurodegenerative disorders suchas Huntington's disease and Parkinson's disease to drug addiction.
Thomas had been studying the roles of histone acetylation inHuntington's disease and began to wonder whether similar mechanisms of generegulation might also be important in schizophrenia. In both diseases, pastresearch in the Thomas lab had shown that certain genes in sufferers were muchless active than in healthy people. "It occurred to me that we see the samegene alterations, so I thought, 'Hey, let's just try it,'" she said.
Working with lead author Bin Tang, a postdoctoral fellow inher lab, and Brian Dean, an Australian colleague at the University of Melbourne,Thomas obtained post-mortem brain samples from schizophrenic and healthy brainsheld at medical "Brain Banks" in the United States and Australia. The brainscome from either patients who themselves agreed to donate some or all of theirbodies for scientific research after death, or from patients whose familiesagreed to such donations.
Much epigenetic research has focused on chemical alterationsto DNA itself. Histone alterations have been much more difficult to studybecause such research requires that the histones and DNA remain chemically intact.Many researchers feared that these bonds were disrupted in the brain afterdeath, according to Scripps. However, Thomas's group was able to develop a technique for maintainingthe histone-DNA interactions.
"While many people thought this was lost, we wereable to show that indeed these interactions are preserved inpost-mortem brain, allowing us to carry out these studies," Thomas said.
Compared to healthy brains, the brain samples from subjectswith schizophrenia showed lower levels of acetylation in certain histone portionsthat would block gene expression. Another critical finding was that in younger subjectswith schizophrenia, the problem was much more pronounced.
Just what causes the acetylation defects among schizophrenicsubjects—what keeps certain pages of the DNA guide closed—isn't clear, but froma medical perspective it doesn't matter, according to Thomas. If she and other researchers can reliably show that acetylationis a cause of the problem, they can look for ways to open the closed guidepages and hopefully cure or improve the condition in patients.
Thomas sees great potential. Based on the more pronouncedresults in younger brains, she believes that treatment with histone deacetylaseinhibitors might well prove helpful in reversing or preventing the progressionof the condition, especially in younger patients. Current drugs for schizophreniatend to treat only certain symptoms, such as hallucinations and delusions, and thedrugs have major side effects including movement problems, weight gain, anddiabetes. If deacetylase inhibitors effectively treat a root cause of thedisease and prove sufficiently non-toxic, they might improve additional symptomsand provide a major expansion of treatment options.
Interestingly, some of the cognitive deficits that often troubleelderly people look quite similar biologically to schizophrenia, Scripps notes, and both situations share at least some brain abnormalities. So deacetylase inhibitors mightalso work as a treatment for age-related problems, and might even prove aneffective preventive measure for people at high risk of cognitive decline basedon family history or other indicators.
SOURCE: Scripps Research Institute news release

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