[autismo-biologia] Angelman syndrome

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A "Long Shot" Pays Off


Grandmother's Alzheimer's leads scientist to a major breakthrough in
Angelman Syndrome
By Elizabeth McBreen

As a research scientist, Edwin Weeber, Ph.D.
<http://www.cureangelman.org/sab.html#ew> , never thought he would be in a
position to receive fan mail. Weeber, who is currently an Associate
Professor at the University of Southern Florida (USF), has spent his
graduate and post-graduate career conducting research on Angelman syndrome
(AS). After 10 years of research and testing, he has discovered how to
reverse the deficits of the disorder in mice.

Angelman syndrome, first discovered in 1965 by an English doctor, Harry
Angelman, is a disorder that causes severe developmental delays, impedes
speech and motor coordination. Other symptoms such as seizures and
microcephaly affect about 80 percent of patients, according to the Angelman
Syndrome Foundation Web site (www.angelman.org). Not evident at birth, AS is
generally diagnosed after the age of 3 years. Relatively rare, AS affects
between 1 in 15,000 and 1 in 30,000 people, and it is common for patients to
exhibit some of the same earmarks as autism. These can include hand flapping
and a short attention span. Although the two disorders can present similar
symptoms, Weeber says that AS is considered more severe in nature.

Weeber started out as a graduate student studying microbiology at Baylor
College of Medicine in Texas. Because his grandmother was suffering from
Alzheimer's at the time, he was drawn to research of the brain, specifically
learning and cognitive ability. Weeber began working with David Sweatt,
Ph.D., who was conducting cognitive studies in his lab. While working in
Sweatt's lab, Weeber became particularly interested in the hippocampus, a
part of the brain that plays a role in memory. Down the hall from Sweatt's
lab, another researcher was studying AS in mice models. "Angelman syndrome
is a maternal imprinted disorder and there are no expressions of it in some
parts of the brain - one of these is the hippocampus. So instead of studying
random things in the hippocampus, I decided to study Angelman syndrome,"
says Weeber.

Prior to Weeber's studies, most of the research that had been conducted on
AS had been genetic. The gene that carries the disorder was identified in
1997. Abnormal function in this gene, UBE3A, had been targeted as a possible
cause for the disorder. UBE3A is a gene that is imprinted on the brain,
meaning that the body knows what part of the gene is maternal and what part
is paternal. "We get half of all of our genes from our mother and half from
our father. The deletion or mutation of the mother's gene causes AS," says
Weeber. Interested in the biomedical aspects of the disorder, he began
studying enzymes and proteins in the brain that work with this gene. Weeber
would make his groundbreaking discovery while working in his own lab at
Vanderbilt University.

As he worked with his mice models from Baylor, Weeber discovered that he
could reverse the effects of AS by regulating a particular enzyme, CaMKII.
CaMKII is "an enzyme that is essential for learning and memory, as well as
normal motor learning. We found that one of the biological abnormalities in
AS mice was reduced CaMKII activity. It was known that reduced CaMKII
activity results in neurological deficits. Thus, we concluded that
regulating CaMKII in the mice may reverse their neurological deficits," says
Weeber. When Weeber tested his theory by crossing mice with AS and mice with
a mutation that caused them to retain their CaMKII activity, the resulting
offspring had no AS symptoms. The seizure activity, mental retardation and
problems with motor coordination all disappeared in the mice models. These
results caused Weeber to conclude that the deletion or mutation of the
maternal part of the UBE3A gene caused reduced CaMKII activity, resulting in
AS.

Weeber says that when the activity of CaMKII enzyme is regulated, the
deletion of the maternal part of the UBE3A gene is corrected. He adds that
this enzyme is not produced until after the mice are born. This may also be
the case in humans. Weeber says that this conclusion is an important when it
comes to the treatment of AS. "This suggests that AS is not developmental in
nature, but rather biochemcial. In other words, the brain appears to be
wired correctly, but the change in CaMKII activity prevents the proper
communication between the neurons in the areas of the brain where maternal
UBE3A imprinting occurs."

Six months ago, Weeber, his wife and their son moved to Florida. The couple
has since welcomed a new daughter to the family, and Weeber has taken the
position as Associate Professor at USF. Weeber and his wife, who has a Ph.D.
in neuroscience, feel that a move to USF is a natural progression because
the school is known for its work in cognitive studies. At USF, Weeber will
pursue therapeutic approaches for AS patients. The results found in Weeber's
mice models were obtained through genetic engineering, and so this method is
not applicable to humans. He says that one of the approaches for treating AS
in humans could be a pharmacological one that would modulate CaMKII. Another
possibility is adeno-associated virus (AAV). Weeber explains that this is a
method for introducing foreign genes in neurons of the central nervous
system. AAV can be used to either introduce CaMKII with the same mutation
that was used to rescue the AS mice, or introduce a UBE3A gene that would
take the place of the deleted or mutated maternal UBE3A gene. Weeber plans
to begin researching the use of AAV to treat AS in the next six months.

While Weeber's discovery has many positive implications for AS patients, it
could also be good news for people with autism. He says that while AS
patients and autistic people look very different, there are genetic
similarities. "Future research may in fact find a relationship between
changes in UBE3A and autism," says Weeber. Other disorders having to do with
cognitive function may also benefit from his research. For now, parents of
AS children are celebrating Weeber's work. Terry Jo Bichell is a Visiting
Scholar at Vanderbilt Kennedy Center for Research on Human Development and
the mother of a nine-year-old boy with AS. Bichell took a position at
Vanderbilt not long after Weeber's article was published. "I suddenly
realized that concentrating on a cure for AS was not a pie-in-the sky day
dream, but a real possibility," says Bichell. "Now it feels like the answer
lies just beyond a flimsy curtain. It is almost in sight."

For more of this article please subscribe to Spectrum
<http://spectrumpublications.com/>  today.

 



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