Take the trouble to read this. It
may not be the whole answer to the confounding problem of schizophrenia, but it
is certainly an identified physical abnormality that can plausibly be
adjusted. There may even be a chemical
pathway of causation before we are finished that we can take control of.
It is all early days, but recall
that we were just as blind and confused with Alzheimer’s before physical
markers were located in the brains of victims.
In fact this particular pathway
is promising in that it suggests that a complete cure could be possible through
restoration of cellular function and balance.
Where scar tissue merely shows the irreversible end result of trauma,
this shows the result of a simple failure to perform or the result of and over
excitation. If we are lucky, it turns out to be that easy.
Brain Cell Malfunction in Schizophrenia Identified
ScienceDaily (Dec. 28, 2011) — Scientists at The Scripps Research
Institute have discovered that DNA stays too tightly wound in certain brain
cells of schizophrenic subjects. The findings suggest that drugs already in
development for other diseases might eventually offer hope as a treatment for
schizophrenia and related conditions in the elderly.
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, a potentially devastating mental disorder
associated with hallucinations, delusions, and emotional difficulties, among
other problems.
"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."
A Promising New Field
Over the past few years, researchers have increasingly recognized
that cellular-level changes not tied to genetic defects play important roles in
causing disease. There is a range of such so-called epigenetic effects that
change the way DNA functions without changing a person's DNA code.
One critical area of epigenetic research is tied to histones. These
are the structural proteins that DNA has to wrap around. "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.
A Good Idea
Thomas had been studying the roles of histone acetylation in
Huntington's disease and began to wonder whether similar mechanisms of gene
regulation might also be important in schizophrenia. In both diseases, past
research in the Thomas lab had shown that certain genes in sufferers were much
less active than in healthy people. "It occurred to me that we see the
same gene alterations, so I thought, 'Hey, let's just try it,'" she said.
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
A great deal of epigenetic research has focused on chemical alterations
to DNA itself. Histone alterations have been much more difficult to study
because such research requires that the histones and DNA remain chemically
intact. Many researchers feared that these bonds were disrupted in the brain
after death. However, Thomas's group was able to develop a technique for
maintaining the histone-DNA interactions. "While many people thought this
was lost, we were able to show that indeed these interactions are preserved
in post-mortem brain, allowing us to carry out these studies," said
Thomas.
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.
Need for New Treatment Options
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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