Aggie awarded grant for Angelman syndrome research

COLLEGE STATION, TX - Dr. Scott Dindot, assistant professor in the Veterinary Pathobiology department at the Texas A&M University College of Veterinary Medicine & Biomedical Sciences (CVM) has been awarded a research grant totaling about $100,000 for Angelman syndrome (AS) research.

AS is a moderately rare disorder, affecting 1 in 12,000 individuals in the United States. It is characterized by mental retardation, speech impairment and motor dysfunction. It is caused by the absence or loss of function of the maternal copy of the UBE3A gene, which is present on chromosome 15 in humans. This gene encodes a protein called E6-AP. However, how the absence of this protein leads to the syndrome's clinical manifestations is not known.

As a step toward resolving this puzzle, Dindot is working on determining the function of this protein.

The one-year grant awarded by the Angelman Syndrome Foundation will fund a project Dindot will begin in January 2010 at the CVM.

The project will be the continuation of a study Dindot worked on as a postdoctoral researcher at the Baylor College of Medicine. In this study, his research group showed that the E6-AP protein may be essential for the normal development of nerve structures called dendritic spines.

Dendritic spines are components of synapses (or synaptic connections), which are junctions through which neurons (or nerve cells) communicate with each other.

It is believed that changes in the number, size and shape of dendritic spines affects cognitive functions, such as learning and memory, through a process called synaptic plasticity.

"As we learn, as we add information to our brain, we strengthen synaptic connections [this process is called synaptic plasticity], which is manifested by dendritic spines becoming larger," Dindot explained.

Dindot's previous study showed that in adult models of mice with AS (that did not produce the protein E6-AP in their neurons), dendritic spines were immature in morphology and number. Also, in mice without the syndrome, E6-AP was observed to be present in dendritic spines.

Taken together, these findings indicated that E6-AP plays a role in dendritic spine development.

The focus of Dindot's upcoming project will be on determining which of the three isoforms of the human E6-AP protein is associated with dendritic spine development.

"We will culture hippocampal neurons [which are involved in learning] from Angelman syndrome mice," Dindot said, explaining the experimental method of the project. "Then, we will express each of the three isoforms of the human E6-AP protein in these cultured neurons and see which isoform of the protein can rescue or fix the dendritic spine defect in these mice."

According to Dindot, identifying which isoform of the E6-AP protein is associated with the dendritic spine defect can form the theoretical basis of some sort of therapeutic intervention for this disease, for example, gene therapy [replacing the defective UBE3A gene with a normal gene] or developing drugs that induce the expression of the E6-AP protein.

"What makes the E6-AP protein so important," Dindot said, "is that the gene that encodes it [that is, UBE3A] is a major player in neurodevelopmental disorders." He explained how this gene is involved in not only AS but also autism.

"Chromosome 15q duplication syndrome is the duplication of the UBE3A gene and the region on the chromosome in which it is present. When this defect is maternally inherited, it is the most common cytogenetic abnormality associated with autism. So not only does UBE3A give rise to AS when absent, when it is present in excess, presumably it gives rise to autism."

Another reason for Dindot's interest in AS is that it is a disorder that involves "genomic imprinting" and "epigenetics," two genetic phenomena he has been curious about since his PhD days.

"Angelman syndrome arises only through mutations [caused by changes in the DNA sequence of a gene] or epimutations [caused by changes in epigenetic modifications] inherited from the mother," Dindot said. "When these mutations are inherited from the father, there is either no disorder or a completely different disorder called Prader-Willi syndrome. This is due to a phenomenon called genetic [or genomic] imprinting."

Dindot elaborated on the epigenetic cause of the syndrome.

"Epigenetics has to do with the regulation of genes," he explained. "There are kids with AS that have no genetic mutation altogether. But instead they have abnormal epigenetic modifications at a regulatory element responsible for driving the expression of the [UBE3A] gene, which turns the gene off. So you end up with the Angelman syndrome despite not having a mutation in the UBE3A gene."

Commenting on the broader scope of his research, Dindot said that his lab is interested in "studying the epigenetic regulation of the gene that causes Angelman syndrome."

Grateful for being selected as one of the six recipients of grants awarded by the Angelman Syndrome Foundation this year for research on this disorder, Dindot said that the funds will be used for purchasing reagents and building his team. In the end, he hopes that his work will be a step toward achieving the goal of the foundation, which is to find a cure for this disease.

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