Molecular Cause of Mental Retardation Traced in Angelman Syndrome

A rare but serious genetic disorder, Angelman syndrome (AS) causes a constellation of developmental problems in children, including mental retardation, lack of speech, and in some cases, autism. More than a decade ago, researchers found that the disease was caused by mutation of a single gene, but no one had been able to explain how the defect—the loss of an enzyme that regulates protein turnover in the brain—results in the debilitating neurological symptoms of AS.

New work from Michael Greenberg, the Nathan Marsh Pusey professor of neurobiology and chair of that department at HMS, provides insight into the mystery by showing that the enzyme, Ube3A, acts on a key protein in nerve cells to control the molding of cell-to-cell connections, or synapses, in response to environmental input. Loss of Ube3A interferes with the brain’s ability to use environmental experience to fine-tune neuronal circuits, which could explain the devastating developmental deficits that occur in AS.

The study, published in the March 5 Cell, opens up new targets for potential therapies for Angelman syndrome, which affects one in 15,000 newborns. Currently, doctors can manage some symptoms, but there is no treatment for the core features.

“With this work, we’ve gone from a place where we could only imagine how Ube3A might work to being able to think about possibilities for therapeutic intervention in a disorder where, until very recently, there was little that could be done,” said Greenberg.

The Ube3A gene is also mutated in some cases of autism, and the new work could lead to a better understanding of some of the problems that occur in autism spectrum disorders, which are 100 times more common than AS.

During the first few years of life, the brain undergoes rewiring based on interaction with the outside world via sensory and other input. This tweaking of neuronal connections is critical to establish normal neurological function and is thought to go awry in multiple developmental disorders that lead to mental retardation or other cognitive problems. The new work suggests that Ube3A is a key regulator of this remodeling process and ties the loss of Ube3A to a specific change in synaptic function.

Under normal conditions, the Ube3A enzyme tags cellular proteins for destruction, and co–lead author Paul Greer, a postdoc in Greenberg’s lab, identified the synaptic protein Arc as one of its targets. Arc is rapidly produced after synaptic activity and serves to dampen neuronal signaling by decreasing the number of neurotransmitter receptors in the synapse. In young mice, Greer found, a new environment triggered the expected production of Arc and a later surge in Ube3A that helped remove Arc before too many receptors were lost. In the absence of Ube3A, Arc was not as effectively removed and accumulated to higher than normal levels. This caused an abnormal lowering of synaptic neurotransmitter receptors, effectively decreasing neuronal communication and disrupting proper development.

The Arc connection has revealed surprising links to other disorders, Greenberg said. In Fragile X syndrome, a major form of inherited mental retardation, neurons also have an overabundance of Arc protein. Although the excess Arc occurs through a different mechanism independent of Ube3A, the two diseases seem to converge on a common synaptic defect. That means new treatments now under study for Fragile X may someday be useful for Angelman syndrome, Greenberg said.

The work may also suggest additional therapeutic targets for AS. As part of the study, the researchers identified several proteins regulated by Ube3A in addition to Arc, some of which might be involved in creating the complex features of AS. “It could be that affecting Arc levels may be useful for some of the symptoms of AS, while modulating other targets will be useful for others,” Greer said. “We are hoping to identify many substrates upon which Ube3A is acting, and one can imagine doing targeted therapeutics on several of them.”

For more information, students may contact Michael Greenberg at meg@hms.harvard.edu.

Conflict Disclosure: The authors declare no conflicts of interest.

Funding Sources: National Science Foundation, National Institutes of Health, Angelman Syndrome Foundation