Grant Research

Jason Yi and Harrison Gabel each receive SFARI Pilot Awards to study autism-related disorders

The Simons Foundation Autism Research Initiative (SFARI) has awarded pilot grants to Assistant Professor Jason Yi, PhD, and Associate Professor Harrison Gabel, PhD, both faculty members in the Department of Neuroscience at Washington University. The awards each total $300,000 over two years, and the labs will use the funds to investigate genetic diseases that result in autism.

photo of jason yi

The Yi Lab studies UBE3A, a ubiquitin ligase that underlies Angelman Syndrome, which causes intellectual disability, epilepsy and a happy disposition. While Angelman is caused by a loss of function of UBE3A, Yi’s group discovered that a gain of function of the protein can also cause neurodevelopmental conditions such as autism.

There are no treatments for Angelman or other UBE3A-related syndromes, and the scientific community has largely considered UBE3A out of reach as a target for drug intervention. That’s because the relevant parts of the protein—its interaction surfaces—are too large for small molecule drugs. Research from the Yi Lab suggests otherwise: they’ve identified particular genetic variants that inhibit or stimulate the activity of UBE3A. Zeroing in on the location of these mutations in the protein will allow them to develop inhibitors at these sites and turn off overactive versions of UBE3A.

“Our work will demonstrate that targeting ubiquitin ligases for therapy is possible using variant-based approaches,” said Yi. “This research has potential to treat neurodevelopmental disorders driven by excessive UBE3A activity.”

The Gabel Lab is a leader in advancing the understanding of neurodevelopmental disorders caused by disruption of gene regulatory proteins, including MeCP2, which leads to Rett Syndrome. Loss of MeCP2 causes widespread changes in gene expression in brain cells. The SFARI award will enable Gabel’s group to probe the transcriptional effects of absent MeCP2 on neuronal subtypes within the cells’ anatomical context.

Harrison Gabel

Other techniques to assess transcriptomics lack throughput or disrupt cells’ environments. Gabel’s team is working with Dr. Andreas Burkhalter, Professor of Neuroscience, to implement what’s known as a cortical flatmount of a mouse brain for spatial transcriptomic analysis—imagine an orange peel cut around the edges and spread out on a plane. Using this tissue preparation, they will be able to trace connections between cells while analyzing transcriptional profiles of hundreds of genes cell-by-cell. Not only will this work illuminate gene dysregulation of various cell types in a model of Rett Syndrome, but in comparisons to wild-type mice, the approach will “provide insights into the normal cellular architecture of cortical neuronal subtypes at unprecedented resolution,” Gabel said.