Young Investigator Research Grant

Paula Ladd, PhD

University of California, San Diego
Deconstructing the transcriptional dysregulation of Spinocerebellar ataxia type 7 retinal degeneration

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurological disorder that leads to progressive loss of neuronal function in discrete regions of the brain resulting in loss of coordinated movement, as well as progressive blindness. The mutation is dynamic, meaning it changes size, most commonly lengthening from one generation to another. Typically, the larger the CAG repeat expansion, the earlier the age-at-onset and the greater the severity of disease.

My objective is to understand what is happening inside the cell as a result of this mutation. By comparing normal, or wild type mice to mice engineered to have the SCA7 disease, I can identify differences are apparent between how the normal versus mutated cells function. Thanks to the engineered SCA7 mice, our laboratory understands that the gene involved with SCA7, Ataxin-7, associates with a large complex of proteins called the STAGA complex. As a group, Ataxin-7 and the STAGA complex regulate other genes within the retina. When Ataxin-7 carries the CAG repeat expansion cannot able to regulate its target genes, resulting in the target genes being turned off in the retina ultimately leading to blindness.

How the CAG repeat expansion interferes with normal Ataxin-7 and STAGA complex function is still not fully understood. My hypothesis is that the Ataxin-7 protein can associate with the STAGA complex whether containing normal or expanded CAG repeats, however, its activity is compromised. I propose to interrogate the proteins that interact with Ataxin-7 and the STAGA complex, including a group of proteins called histones and RNA polymerase II. This analysis will help us to understand how the CAG repeat expansion impairs STAGA complex function and will have important implications for the development of therapies to treat SCA7.