Dr. Valerie Hu* is researching metabolic pathways implicated in autism. |
I’ve written about
Valerie Hu’s work before. Dr. Hu is originally from Hawaii and is currently a
molecular biologist at George Washington University (GWU). She is passionate
about researching metabolic pathways for autism. Finding these pathways can lead to possible
symptom amelioration or even a cure…and one key reason Dr. Hu is passionate
about her work is because her own son is severely afflicted by autism. Knowing autism firsthand is to witness your
child suffering on a daily basis, unable to communicate and frequently in
pain.
Dr. Hu has been
researching a gene called Retinoic acid-related Orphan Receptor-Alpha (RORA),
which controls the production of an enzyme called aromatase, which converts
testosterone to estrogen. In 2010, Dr.
Hu and her colleagues found that the brains of autistic people have low levels
of a protein produced by the RORA gene and that RORA interacts with types of
testosterone and estrogen found in the brain.
From Psychology Today: RORA is involved in
several key processes implicated in autism, including brain cell (Purkinje)
differentiation; muscle tone and development of the cerebellum; protection of
neurons against chemical stress; suppression of inflammation; and regulation of
circadian rhythm. In research on twins
published last year, the expression of RORA was indeed shown to be affected by
a key epigenetic factor (methylation).
This explains how one pair of otherwise identical twins can be autistic
but the other not. Although identical
twins may share the same genes, they may vary in their expression.
In Dr. Hu's tests, the presence of testosterone made RORA less active, which
led to a loop of aromatase levels declining thereby increasing testosterone
accumulation; estrogen had the opposite effect.
This gene may explain the extreme gender imbalance in autism occurrence;
boys are affected 4 to 5 times more often than girls. Dr. Hu postulated that
higher levels of estrogen in girls may help to protect them from developing
autism.
In her latest
research, recently published in Molecular
Autism, Dr. Hu and her
co-author Dr. Tewarit Sarachana found that RORA encodes a protein that can
regulate the expression of over 2,500 other genes, and of these genes, many are
known to affect neuronal development and functions. Neurons are electrically excitable cells that
are the building blocks of the central nervous system, processing and
transmitting information.
What is
particularly exciting is 426 of RORA’s gene targets are already listed in
AutismKB, a database of known autism candidate genes. I won’t pretend to understand the scientific
techniques Drs. Hu and Sarachana used, but they were able to confirm through
their testing that RORA does regulate six genes, and when RORA levels are cut
in half, these genes also reduce their expression. Further, the expression levels of these six
genes were confirmed to be reduced in their expression in RORA-deficient
post-mortem brain tissues from individuals with autism when compared with
age-matched, non-autistic controls.
Dr. Hu says, “We
see it as a domino effect, where RORA is a particularly shaky domino. If knocked over, it can also knock down a
whole bunch of other genes, except that it’s not just a single chain of
events. There are multiple chains of
events, leading to massive disruption of gene expression in autism.”
Dr. Hu’s work is
promising for several reasons. If the
pathways that are disrupted in autism are understood, there is hope for a cure.
I’ve had folks from
the neurodiversity crowd tell me children with autism aren’t suffering and that
it’s simply a differently-wired brain that does not need to be cured, so before
anyone goes there let me say I’m not talking about high-functioning autism
here. I’m talking about the kids who are
NOT quirky geniuses who think in pictures, but rather those who suffer with
painful gastrointestinal symptoms, epileptic seizures, mitochondrial disorders,
autoimmune conditions such as mastocytosis and diabetes, and severe
allergies. Those who are unable to
communicate their basic needs…who are not toilet trained. These kids do suffer--mine included.
* Dr. Hu received her Ph.D. in Chemistry from Caltech and did her
postdoctoral research in Membrane Biochemistry and Immunology at UCLA.
More information about her research and papers can be obtained at: http://www.gwumc.edu/biochem/faculty_vhu.html
References:
http://www.psychologytoday.com/blog/the-imprinted-brain/201102/rora-just-the-gene-autism-we-wanted
Sarachana
T., Xu M,. Wu R.C., Hu V.W. (2011). Sex hormones in autism: androgens and
estrogens differentially and reciprocally regulate RORA, a novel candidate gene
for autism. PLoS
One. 2011;4:e17116. doi:
10.1371/journal.pone.0017116.
Sarachana,
T. & Hu, V. (2013). Genome-wide identification of transcriptional targets
of RORA reveals direct regulation of multiple genes associated with autism
spectrum disorder. Molecular Autism.
2013. doi:10.1186/2040-2392-4-14.
Xu,
L.M., Li, J.R., Huang, Y., Zhao, M., Tang, X. & Wei, L. (2012). AutismKB:
an evidence-based knowledgebase of autism genetics. Nucleic Acids Res, 40,
D1016-1022.
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