Children with Angelman syndrome are often seen laughing and smiling, but this cheerful demeanor masks serious neurological problems -- mental retardation, movement problems and seizures.
New research in mice, however, suggests that many of these deficits could be alleviated.
Edwin Weeber, Ph.D., and colleagues reversed the neurological deficits in a mouse model of Angelman syndrome by preventing the inhibition of CaMKII, an enzyme highly expressed in brain regions affected by Angelman syndrome.
The results, which appear in the March issue of Nature Neuroscience (currently available online), reveal an important part of the mechanism underlying the condition and point to potential therapeutic targets for treating these symptoms.
Angelman syndrome, which affects approximately one in 15,000 children, is a debilitating neurological disorder characterized by mental retardation, severely limited speech, and movement and balance problems.
In 1997, researchers determined that Angelman syndrome was caused by a mutation in a single gene, called UBE3A. They subsequently developed a mouse model of Angelman syndrome by mutating this gene.
But the finding was baffling, said Weeber, because UBE3A is a "housekeeping" gene, meaning that it broadly regulates cellular processes not particularly specific for any of the neurological deficits seen in these children. Specifically, the protein encoded by UBE3A "tags" other proteins for degradation by the cellular "garbage disposal," the proteasome.
"The most difficult thing to rationalize was that this housekeeping gene -- which nobody thought did anything -- caused severe mental retardation," said Weeber, an assistant professor of Molecular Physiology and Biophysics and Pharmacology and senior author on the study.
"So we started trying to identify some of the protein's molecular targets."
In the process, Weeber and colleagues identified an abnormality in the Angelman syndrome mouse model -- changes in an enzyme called calcium/calmodulin-dependent protein kinase II (CaMKII), which is important in the cellular processes that underlie learning and memory.
They found that, in Angelman syndrome, CaMKII activity was reduced due to an inhibitory chemical modification (phosphorylation). Because of CaMKII's prominent role in neuronal function, Weeber suspected that this might account for many of the neurological deficits seen in Angelman syndrome children.
Fortuitously, one of Weeber's colleagues -- Ype Elgersma, Ph.D., at Erasmus Medical Center in Rotterdam, Netherlands -- had created a mouse with a mutation that prevented this inhibition of CaMKII.
The researchers decided to breed the Angelman mice with the CaMKII mutant mice to see if counteracting the CaMKII inhibition would alleviate the neurological problems.
The researchers then ran the resulting "double mutants" through a battery of neurological and cognitive tests.
Angelman mice performed poorly on learning and memory tasks and displayed impaired motor coordination.
The double mutants, however, showed normal learning and memory and motor coordination. And while the Angelman mice were also prone to seizures, the double mutants showed very low seizure susceptibility.
Weeber was surprised by the robust results. "We thought we might rescue some of the deficits that we saw in the mouse model," he said. "We had no idea that we were going to rescue basically everything."
Although impossible to apply the genetic engineering used in the current study to correct these deficits in mice to humans, Weeber thinks that the findings may point to new therapeutic targets for the disorder.
"It's very conceivable that if we can figure out what lies between UBE3A and CaMKII -- and if it's a specific path -- then that could be a therapeutic target."
But the results may apply more broadly, Weeber said, to other types of mental retardation syndromes that remained unexplained and untreatable.
"There are a lot of mental retardation syndromes that we still don't understand. Maybe the changes in CaMKII associated with Angelman syndrome could be implicated in other mental retardation syndromes as well."
Weeber is also an investigator in the Vanderbilt Kennedy Center for Research on Human Development.
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