Innovative research projects for 2016

Thanks to the generous support of the AS community, the Angelman Syndrome Foundation has funded groundbreaking research proposals, each focusing in a different and very important area of AS research.

These studies take unique approaches to further understanding the complexities of Ube3a and how the paternal copy can best be reactivated. The extensive study about anxiety in individuals with AS is a first for AS research and refining the overall picture of the significant role that anxiety does play in AS.

Understanding how Angelman Syndrome Neurons Perform in the Brain

Dr. Eric Levine – University of Connecticut School of Medicine

Imagine a traffic light at a busy intersection: when working correctly, the traffic light directs vehicles where they need to go and traffic flows properly. In the brain, the “traffic lights” control the signaling at synapses, which are the intersections between brain cells, or neurons. In an individual with Angelman syndrome, the flow of information at certain synapses is not regulated properly, leading to symptoms such as developmental delay, seizures and movement disorders.

In order to study the molecular mechanisms that are responsible for the symptoms of Angelman syndrome, this research will use a recently discovered technique that allows skin or blood cells from individuals to be converted into brain neurons that can be studied in the laboratory. For the first time, the research team will be able to evaluate the intersections (synapses) of human Angelman syndrome neurons at a cellular level. These studies will focus on a process called synaptic plasticity that adjusts the strength of synaptic intersections. The synaptic plasticity process plays an important role in forming proper neuronal circuits during brain development, and it is also critical for learning and memory throughout life. The research team will determine whether signaling malfunction by the molecule BDNF (the “traffic light”) causes deficits in the synaptic plasticity process in Angelman syndrome neurons. Issues with BDNF signaling could be responsible for the language impairments, seizures, and other symptoms of Angelman syndrome.

This research is important because it will:

  • Identify a novel role for the molecule BDNF in the synaptic signaling process in individuals with Angelman syndrome.
  • Provide a platform for screening potential therapeutics in human neurons.

Understanding Ube3a Isoforms

Dr. Ype Elgersma – Erasmus MC, Rotterdam, The Netherlands

The UBE3A protein has two variants called isoforms. This information has been known for some time, but only recently, research discovered that these two isoforms of UBE3A travel to different locations in the brain. The research team is applying this new knowledge to understand the basis of Angelman syndrome.

In typically developing humans, one of the UBE3A isoforms travels to the synapse, where neurons intersect in the brain and are told what to do. With the recent discovery, we now know the other UBE3A isoform goes to the nucleus of the neuron, where DNA is located.

These two isoforms work together for normal brain functionality. In individuals with Angelman syndrome, we know that UBE3A is not functioning properly (or entirely absent), but we do not know which isoform of Ube3a is responsible for causing Angelman syndrome, if not both.

Using this new knowledge, the research team will evaluate two types of mice: one missing the synapse isoform but keeping the nucleus isoform, and another missing the nucleus isoform but keeping the synapse isoform. This approach allows the team to research how each isoform impacts the mice, possibly shedding light on the importance of each isoform’s function.

This research is important because it will potentially:

  • Identify the importance of UBE3A isoforms in Angelman syndrome brain development.
  • Determine if the synapse isoform and/or if the nucleus isoform has greater impact on brain development, helping future research narrow its focus on which isoform is most important.

Finding new ways of Unsilencing Ube3a with CRISPR/Cas9

Dr. Mark Zylka – UNC-Chapel Hill

Based on previous research conducted at Dr. Mark Zylka’s lab and Dr. Ben Philpot’s lab, Dr. Zylka’s team will continue this work with the goal of unsilencing the paternal copy of Ube3a using new methods. Past research has shown that topoisomerase inhibitors, a drug compound, can unsilence the paternal copy of Ube3a, but that this drug also affects a number of other genes. Dr. Zylka’s team will use new technology (CRISPR/Cas9 screening technology) and a new approach to unsilence Ube3a, called a genetic screen. We know there are more than 20,000 genes in the human genome, and this genetic screen will evaluate each of those genes to see if any of them can unsilence the paternal copy of Ube3a. This is a novel new approach that has not been conducted before. In the end, the research team hopes to have a list of genes that can unsilence paternal Ube3a with little to no impact on other genes during the process.

Why this research is important:

  • We know from previous research that unsilencing Ube3a using specific drugs can affect a number of other genes in the process.
  • This research, using CRISPR/Cas9 screening technology and a new approach to unsilencing Ube3a, will look for genes—rather than drugs—that can unsilence paternal Ube3a with little to no impact on other genes during the process.

See more about CRISPR/CAS9 technology.

Understanding the ability for Learning Improvement if Ube3a is Restored in a Later Life Stage

Dr. Geeske van Woerden – Erasmus MC, Rotterdam, The Netherlands

Dr. Geeske Van Woerden and her lab will research the best time to correct certain symptoms of AS when Ube3a is restored in a mouse model. Overall, the research team attempts to answer the question: can certain behaviors or symptoms of AS be reversed by activating Ube3a, at any life stage? Additionally, Dr. Van Woerden’s team will seek novel new tools for learning/intellectual abilities for drug testing.

To accomplish this, the research team will use an AS mouse model and evaluate the ability of mice to learn specific tasks. The mice are genetically modified to be born with AS, and they experience the symptoms of AS throughout their entire life. The research team will use a list of specific tasks to see if the AS mice have difficulty learning a particular task. If a particular task stands out among others as more difficult to learn, the research team will then use another mouse model and activate the Ube3a gene. The team will then re-evaluate the mice’s ability to learn that specific difficult task once Ube3a is activated. This will help the team understand the chances for cognitive or learning improvement if Ube3a is restored in a certain life stage. This research will help answer the question about the importance of the Ube3a gene at different life stages and with different learning abilities or behaviors. Additionally, this will result in a novel cognitive behavioral task that will allow us to study the effect of new drugs on learning/intellectual abilities in AS mice.

This research is significant because it will:

  • Help understand the chances for cognitive or learning improvement if Ube3a is restored at a certain life stage.
  • Result in a novel tool for learning/intellectual abilities to be able to test new drugs in AS mice.

These two items will help AS researchers understand the optimal window to restore Ube3a in an AS mouse model to best improve cognition and learning abilities.

Evaluating Anxiety in Individuals with Angelman Syndrome

Dr. Christopher Keary – MassGeneral Hospital for Children

Many families of individuals with Angelman syndrome express concern to their doctors about anxiety in their loved one. However, very little is understood about anxiety in individuals with AS at the clinical level. Many clinicians feel that once physical symptoms of AS are managed, emotional symptoms of AS (such as anxiety) remain that are much more difficult to evaluate, or even treat. With this research project, Dr. Keary seeks to find ways to assess and measure anxiety in individuals with AS, which has never been done before. Having a better understanding of anxiety in AS is an important step towards developing future treatment strategies for anxiety in individuals with AS and improving their quality of life.

To accomplish these goals, Dr. Keary will conduct in-person meetings with individuals with AS and their family members/caregivers to perform evaluations to assess for anxiety. Dr. Keary will assess and measure using:

  1. Standardized tools for measuring anxiety that are validated in individuals with developmental disabilities.
  2. Standardized tools for measuring anxiety that are un-validated in individuals with developmental disabilities. In order for tools to become commonly used and accepted (validated), they have to be tested in people with that disorder—many haven’t been tested on individuals with AS, which is what has made it difficult to define the issue.

He will then determine how useful these tools are and how much they coincide with problems the individual is experiencing. Furthermore, Dr. Keary will be exploring if specific genetic types of the diagnosis (deletion +, etc.) affect anxiety differently.