"Oligodendrocyte Dysfunction in Schizophrenia and Bipolar Disorder" ...possible explanation
James Michael Howard
jamesmichaelhoward at anthropogeny.com
Thu Sep 11 09:46:36 EST 2003
Possible Explanation of New Connection of:
Oligodendrocyte Dysfunction in Schizophrenia and Bipolar Disorder
(www.anthropogeny.com/research.html near bottom of page)
Copyright ã 2003, James Michael Howard, Fayetteville, Arkansas, U.S.A.
This is my response to "Oligodendrocyte Dysfunction in Schizophrenia and
Bipolar Disorder, The Lancet 2003; 362: 798-805. It was sent to The Lancet and
to the corresponding author. The "summary" is reproduced at the end of my
The findings of Tkachev, et al., may be explainable as results of low
availability of dehydroepiandrosterone (DHEA). Tkachev reported "downregulation"
of genes controlling myelin production in oligodendrocytes in schizophrenia.
DHEA positively affects myelin in damaged nerves (Microsurgery 2003; 23(1):
49-55 and Microsurgery 2002; 22(6): 234-41). Oligodendrocytes are known to
produce DHEA (Endocrinology 1999; 140(8): 3843-52 and Journal of Neurochemistry
2000; 74(2): 847-59). Schizophrenics exhibit significantly low DHEA (Biological
Psychiatry 1973, 6: 23).
In 1985, I first suggested schizophrenia and Alzheimer's disease result from low
DHEA (A Theory of the Control of the Ontogeny and Phylogeny of Homo sapiens by
the Interaction of Dehydroepiandrosterone and the Amygdala). (At the time, I was
not aware of Biological Psychiatry 6: 23 and the first reports (three in the
same year) of low DHEA in Alzheimer's disease did not appear until 1989 in
Lancet.) Tkachev, et al., also report that other research has "not shown
myelin-related gene expression changes" in Alzheimer's disease, among other
neuropathies. My prediction of the effects of low DHEA in schizophrenia and
Alzheimer's disease are derived from my principal hypothesis that evolution
selected DHEA because DHEA optimizes replication and transcription of DNA. (In
fact, it is my hypothesis that mammals evolved because of DHEA, "Hormones in
Mammalian Evolution," Rivista di Biologia / Biology Forum 2001; 94: 177-184 and
is very important to human evolution, "Androgens in Human Evolution. A New
Explanation of Human Evolution," Rivista di Biologia / Biology Forum 2001; 94:
345-362.) It followed that all tissues, especially those of the brain, are
directly affected by levels of DHEA. Among some other diseases of the nervous
system, I attempted to demonstrate a connection of low DHEA with schizophrenia,
Alzheimer's disease and depression. (A connection of depression with low DHEA
has since been supported.) I was suggesting that these neuropathies represent
reduced transcription, or "downregulation," of genes as causes of these
diseases. I was pleased to read Tkachev, et al. Now, according to my
explanation, different genes that are vulnerable to the effects of low DHEA will
fail to function properly according to their vulnerabilities. Therefore, as
Tkachev, et al., report, the effect is not the same in all tissues and all
diseases. However, DHEA naturally begins to decline around twenty to
twenty-five, reaching very low levels in old age. I suggest this loss of DHEA
begins to expose genes which do not function well during times of low DHEA and
this combination may account for many diseases which appear near or subsequent
to age twenty. This may also explain the findings of Tkachev.
Lancet 2003; 362: 798-805
Background Results of array studies have suggested abnormalities in expression
of lipid and myelin-related genes in schizophrenia. Here, we investigated
oligodendrocyte-specific and myelination-associated gene expression in
schizophrenia and bipolar affective disorder.
Methods We used samples from the Stanley brain collection, consisting of 15
schizophrenia, 15 bipolar affective disorder, and 15 control brains.
Indexing-based differential display PCR was done to screen for differences in
gene expression in schizophrenia patients versus controls. Results were
cross-validated with quantitative PCR, which was also used to investigate
expression profiles of 16 other oligodendrocyte and myelin genes in
schizophrenia and bipolar disorder. These genes were further investigated with
an ongoing microarray analysis.
Findings Results of differential display and quantitative PCR analysis showed a
reduction of key oligodendrocyte-related and myelin-related genes in
schizophrenia and bipolar patients; expression changes for both disorders showed
a high degree of overlap. Microarray results of the same genes investigated by
quantitative PCR correlated well overall.
Interpretation Schizophrenia and bipolar brains showed downregulation of key
oligodendrocyte and myelination genes, including transcription factors that
regulate these genes, compared with control brains. These results lend support
to and extend observations from other microarray investigations. Our study also
showed similar expression changes to the schizophrenia group in bipolar brains,
which thus lends support to the notion that the disorders share common causative
and pathophysiological pathways.
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