Dr. Sean T. Sweeney
University of York

Using Drosophila to understand the role of junctophilin in Huntington’s disease-like 2; a neurodegenerative disease affecting African-Americans.

Huntington’s disease-like 2 (HDL2) is a progressive autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington’s disease (HD). The causal mutation is a CTG/CAG expansion mutation in a variably spliced exon of junctophilin-3. Results to date suggest that all affected individuals are of African or African-American descent. 1-15% of African-American patients who present with HD symptoms but do not have an HD mutation have been found to have mutations in junctophilin-3. The role of junctophilin proteins is at present poorly understood. A role for junctophilin in calcium homeostasis in muscular excitiation/contraction coupling has been elucidated. However, a role for junctophilin in neural tissue has as yet not been studied. We propose to study the role of junctophilin in nerve and muscle tissue using Drosophila, where only one conserved junctophilin gene is present in the genome. We will attempt to generate loss-of-function mutants of the junctophilin gene to further our understanding of its function. We will also generate triplet expansion transgenes of the junctophilin gene in order to understand the neuronal dysfunction generated by the mutant protein. Drosophila has recently been very prominent in key breakthroughs in our understanding of triplet repeat expansion diseases and we intend to use the advanced genetics available in this model system to improve our understanding of HDL2.