Author Date

2024-03-08

Degree Name

Department

Chemistry and Biochemistry

College

Physical and Mathematical Sciences

Defense Date

2024-02-20

Publication Date

2024-03-08

First Faculty Advisor

Kenneth Christensen, BYU

First Faculty Reader

Sarah Woodson, JHU

Honors Coordinator

Walter Paxton, BYU

Keywords

Huntington's Disease, optical tweezers

Abstract

Huntington’s Disease is characterized by an extended (CAG)n repeat found in the huntingtin (Htt) gene. While the typical human contains 6-20 CAG repeats, people with over 36 repeats manifest symptoms of the disease. The extended CAG repeats allow the Htt pre-mRNA transcript to form a hairpin loop structure which can sequester certain vital proteins such as Muscleblind like protein 1 (MBNL1), hindering their functional role. Further understanding the structure of the MBNL1-RNA complex is possible through force spectroscopy, or “optical tweezers”, applied on the single molecule level. Force spectroscopy generates force versus distance plots for individual RNA molecules, revealing the dynamic “slipping” action of the hairpin, in which the hairpin shifts by 3 base pairs. Force spectroscopy assays have not been performed on the MBNL1-RNA complex, or on MBNL1-RNA treated with D6, a DAPI derivative that can intercalate into the RNA hairpin thought to be a potential small molecule treatment for HD. We aim to understand the structures of these complexes and the kinetics of their formation, in the hopes of unveiling potential avenues for developing novel treatments for Huntington’s disease and other trinucleotide repeat expansion diseases.