Rajalaxmi Natarajan, Ph.D.
Sept 6, 2017
An exciting study
published in Science Translational Medicine
from the laboratory of Dr. Huda Zoghbi, director of the
Jan and Dan Duncan Neurological Institute (NRI) at Texas
Children's Hospital, and professor at Baylor College of
Medicine, describes the discovery of new 'druggable' modulators of
methyl-CpG-binding protein 2 (MeCP2), a key neuronal protein. Too
little MeCP2 protein causes Rett syndrome in girls and too much of
it causes MECP2 duplication syndrome, a
progressive neurological disorder in boys.
MeCP2 is one of the "Goldilocks" proteins which means minor
changes in its level can lead to a variety of neurological symptoms
including epilepsy, autism, cognitive dysfunction, and poor motor
function in humans and mice.
Zoghbi's team had previously shown that either deletion of an
extra copy of the MECP2 gene or inhibition of
production of excess MeCP2 protein using antisense oligonucleotides
in mice modeling MECP2 duplication syndrome
normalized MeCP2 levels and reversed most of the symptoms,
surprisingly, even in mature mice that have been symptomatic for
months. Other labs have shown that restoring MeCP2 in neurons
successfully reversed symptoms of Rett syndrome in mice.
Despite successful manipulation of MeCP2 in animal models using
genetic methods, until now, it had been difficult to develop a drug
to directly and precisely modulate the levels of MeCP2 and little
was known about its regulators.
To identify regulators of MeCP2, the authors employed an elegant
strategy using a fluorescent cell-based assay and tested the
ability of all known human kinases and phosphatases, crucial
enzymes that activate or inhibit target proteins, to modulate MeCP2
Four candidate modulators (three kinases and a phosphatase)
emerged from the cell-based screen, two of which were further
validated in mice. To investigate the potential relevance
to MECP2 duplication syndrome, Zoghbi's team
tested the effect of inhibiting these candidate modulators in
transgenic mice that express twice the normal levels of MeCP2 due
to the addition of a copy of the human MECP2
gene. Only one candidate modulator had commercially available
inhibitors, which when administered to those transgenic mice,
reduced MeCP2 levels in the brain and improved their motor
Unintended side effects or cellular toxicity are the main
reasons why many potential drug targets fail to become successful
therapies and it takes decades of further preclinical research to
identify new targets. The strategy described in this study can now
be expanded to screen thousands of druggable targets to identify
those that either decrease or increase MECP2 (to
help solve MECP2 duplication syndrome and Rett syndrome,
respectively). Having a rich source of targets will allow
researchers to select the most efficacious candidate(s) with the
least side effects and will greatly speed up the process of finding
a treatment for MeCP2 disorders.
In addition to the promise it offers for MeCP2 disorders, this
study also provides a blueprint to unearth potential drug targets
for other neurological disorders caused by changes in expression of
a specific protein.