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Tocotrienols reverse IKAP and monoamine oxidase
deficiencies
in
familial dysautonomia
In
August of 2005, Drs. Anderson and Rubin published an article which
provides new insight into a possible cause of dysautonomic crises in
individuals with FD and demonstrates the benefits tocotrienol
supplementation provides for those with FD.
The observed abnormal
processing of neurotransmitters in individuals with FD prompted a
study of the enzymes involved in this process. Anderson and Rubin
reported a reduced presence of monoamine oxidase A (MAO A), an
enzyme critical to the degradation of neurotransmitters, in tissues
derived from individuals with FD. The reduced presence of this
enzyme likely explains the reason emotional or physical stress,
which results in the production of large amounts of
neurotransmitters, can precipitate crises in individuals with FD.
Furthermore, the reduced presence of MAO A likely increases the
sensitivity of those with FD to tyramine, a molecule present in
certain foods, which is normally broken down by MAO A. The reduced
ability of those with FD to process tyramine, which acts as a
nervous system stimulant, likely explains why some with FD go into
crisis after eating tyramine-containing foods. In this publication,
Anderson and Rubin also demonstrate that the ingestion of
tocotrienols by individuals with FD helps to overcome the impact of
the FD-causing mutation and results in the production of elevated
levels of functional IKAP. This increased presence of IKAP is
accompanied by an elevation in MAO A levels whose presence may
explain the observed ability of the tocotrienols to reduce or
eliminate crises in some with FD.
The findings presented in this
publication are extremely significant as they provide new insight
into the triggers for crisis and offer those with FD an
understanding as to how to avoid these life-threatening events. This
publication also extends the earlier studies of Anderson and
coworkers demonstrating the ability of tocotrienols to increase
functional IKAP production in cells derived from those with FD. Now
there is a clear demonstration that supplementation with
tocotrienols increases the amount of functional IKAP present in
individuals with FD.
Breakthrough
at Fordham
University's Laboratory for
Familial
Dysautonomia Research
Just over a year ago, on September 10,
2004, Dr. Berish
Rubin of Fordham University's Laboratory for Familial Dysautonomia
Research shared the discovery of an additional compound that
increases normal IKAP protein expresssion. Supplementation
with tocotrienols, a form of Vitamin E, had already been found by
Rubin's lab in May to increased IKAP gene expression (see related
story below). IKAP is the gene responsible for Familial
Dysautonomia.
The new finding, that EGCG, a
constituent of green tea which works in a different way from
tocotrienols, increases normal protein production was greeted by FD
families with enthusiasm. "If this new substance increases the
effect of tocotrienols, it'll be amazing," said one parent.
Our cells' DNA is made up of
genes. A gene's DNA is copied into RNA, more or less a
template for proteins. In Familial Dysautonomia, the IKAP
gene's mutation can be ignored some of the time and gene produces
normal RNA; this occurs more often in some tissue types (skin) and
less in others (brain). The FD mutation is not in the actual protein
template region of the gene known as the exon, but in the intron,
the command part which tells the cell how to cut and paste the RNA.
To increase the amount of normal protein, a substance can either
turn up the amount of gene expression in general, causing more
normal and more abnormal protein, or a substance can get the gene to
be cut and pasted correctly by ignoring the mutation.
Tocotrienols (or
tocos as they are called by most of the children taking the
supplement) work by getting the cell to turn up expression of the
gene in general, so that both normal and abnormal RNA are increased;
it revs up the gene engine. EGCG works by getting the cell to
make more of the normal RNA, thus producing more normal protein; it
makes the cell work more efficiently. The two supplements
should work in a complementary fashion.
EGCG works
specifically by reducing the amount of
hnRNPB1, a protein that binds
to the two Exon Splicing Suppressors (ESS) of exon 20. When
hnRNPB1 is
bound to the ESS, the RNA produces less normal protein. By
decreasing the binding protein, an increase in the normal form of
IKAP results.
Because different versions of
green tea and green tea extract have varying amounts of EGCG and
some supplements include substances that can decrease normal IKAP
protein production, Dr. Rubin has been working with a nutriceutical
to help develop a product that has maximum and standardized levels
of EGCG, and that does not include any suppressors of normal IKAP.
This product should be available to the public in the near future.
According to
Health
and Fitness Forums, "Epigallocatechin Gallate (EGCG),
protects against digestive and respiratory infections, helps to
block the cancer promoting actions of carcinogens, protects against
high total and LDL cholesterol levels, and blocks the attachment of
the bacteria associated with dental cavities to the teeth."
Click here for Dr.
Rubin's summary of his presentation
Lab Funded by FD Hope Finds Vitamin
Improves Gene Function
The Laboratory for Familial Dysautonomia Research at Fordham
University reported on May 27th that a variant of Vitamin E may be a
possible therapy for Familial Dysautonomia (FD). In an unprecedented
article published online in May’s Biochemical and Biophysical
Research Communications, FD Hope funded researchers Drs. Sylvia
Anderson and Berish Rubin report that tocotrienols can increase the
expression of normal IKAP gene.
The
Search for a Cure
In January, 2001, researchers at Fordham University and at
Massachusetts General Hospital shocked the FD community by reporting
the discovery of the gene mutation that causes FD. After years of
waiting for the identification of the mutation, the scientific
community could now proceed to the search for a cure.
Having discovered the genetic cause of FD, Anderson and Rubin
redirected their laboratory’s research effort in the hope of finding
therapeutic approaches that would benefit the many children and
adults with the disorder who had flocked to their lab in the wake of
the gene discovery.
The researchers used the unique attributes of the mutation that they
had discovered to guide their search for treatment. The genetic
mutation causing FD greatly reduces the amount of functional IKAP
protein produced in affected individuals, but a small amount of
normal protein can be detected. The scientists searched for
substances capable of increasing that amount of functional IKAP
protein.
The team examined hundreds of compounds for their ability to
modulate IKAP expression, with a focus on natural compounds. Of
these, the tocotrienols were capable of significant increase in the
amount of functional IKAP in cells.
Positive Results
Early reports of the supplement have been encouraging, several
individuals with FD taking an over-the-counter supplement that
contains 50 mg of tocotrienols (Twinlab Maxilife Rice Tocotrienols),
the substance reported to increase IKAP expression. Initial reports
indicate a positive effect on the health of the individuals who have
taken tocotrienol.
Rubin and his colleagues see this as a first step towards the
development of therapeutic modalities that will help reverse the
impact of the FD-causing mutation. Anderson reflected her
excitement on the laboratory’s efforts. She said, “It is wonderful
seeing the translation of our laboratory work into something that is
helping the children in a measurable manner.”
Anderson and Rubin were joined in their research by graduate student
Jinsong Qui, the David Rancer Memorial Fellow at Fordham University,
a fellowship established and sponsored by FD Hope in honor of the 11
year old who died as a result of complications of FD in May, 2001.
Individuals in the New York City area who would like to participate
in an evaluation of the effect of tocotrienol supplementation should
contact Dr. Rubin via email at
rubin@fordham.edu.
Totoctrienols induce IKBKAP expression: a possible therapy for
familial dysautonomia. Anderson, Qui, and Rubin, Biochemical
and Biophysical Research Communications 306 (2003) 303-309.
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