Scientists have long searched unsuccessfully for the genetic factors that cause schizophrenia. Now we know why: the disorder is actually caused by what happens in cells around the genes. That knowledge could give us our best treatment yet for schizophrenia.
It turns out that schizophrenia is an example of what's known as an epigenetic effect, which are changes in the body's cells that are not directly tied to genetic defects. These epigentic effects can actually prevent DNA from functioning properly, and these have the potential to cause some truly devastating diseases.
One part of the cell that is particularly susceptible to these epigenetic problems are structures known as the histones, which are structural proteins that DNA has to wrap around. Much like our small intestine has to be tightly coiled within our body to fit it all in, the total length of DNA would never actually fit in any one cell, and so it has to be wrapped around the histones for it to fit at all.
The problem is that DNA needs the equivalent of breathing room for it to function properly - if it's wrapped too tightly, then genes will be effectively cut off and cease to function. That's why the histones have little "tails" that undergo constant chemical transformations to relax the DNA and let it stretch out, and then pack it all back in to conserve space again.
The histones and DNA form little things called chromatin that manage the constant process of relaxation and condensation, which allows different genes to have the space to be expressed at different times. The histones and DNA are constantly changing configurations, sometimes tighter, sometimes looser, and all of these combine together to keep the cell machinery working smoothly.
The problem comes in if the histones stop undergoing a process known as acetylation, which means the chromatin is no longer able to relax the DNA and gives genes room to be expressed. If that happens, the genes remain trapped and are basically shut off, and that epigenetic effect can have huge detrimental consequences on the cell and, if it's widespread enough, the rest of the body.
When this phenomenon happens in brain cells, it can be a key factor in the advent of Huntington's disease, Parkinson's disease, and drug addiction. Now, thanks to scientists at the Scripps Research Institute, we can add schizophrenia to that list.
Part of the trouble in researching the effects of acetylation on the brain is that these can really only be studied after the patients have died, and until now it was though the relationships between histones and DNA are permanently disrupted after death. The Scripps researchers needed to develop an all-new technique to spot evidence of these chemical links in the brain samples donated by various healthy and schizophrenic subjects.
With this new tool in place to track the relationships, the truth soon became clear. The schizophrenic brains showed significantly lower levels of acetylation in certain key histones that would block gene expression. This suggests that, like these other serious mental problems, schizophrenia is in some ways the result of this particular epigenetic effect on top of whatever genetic predispositions a person may have.
What makes the results even more intriguing is that younger brains showed a far more pronounced effect than those of older people. The ability to pick up on this particular factor in schizophrenia as early as possible could be crucial to minimizing, perhaps even reversing, the symptoms of the disorder. Existing drugs to treat schizophrenia tend to have very serious side effects and can only treat a handful of symptoms. Treatments built on this breakthrough could go much, much further than that.
The researchers don't know exactly what is causing this reduced acetylation, but it doesn't matter — once they've confirmed the link between this and schizophrenia, all they need to do is figure out how to get the chromatin working again, and reopen the gateways to allow genes to express themselves. The researchers say there are already drugs in development that could help out with this, which should fast track the process to begin clinical trials.