Mismatch Binding Molecules as Therapeutic Agents for Repeat Expansion Neurodegenerative Diseases

Huntington’s disease (HD) is a neurodegenerative disorder caused by aberrant expansions of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene. These expansions lead to the formation of extended RNA hairpins containing adenine-adenine (A·A) mismatches, contributing to RNA misfolding and toxic gain-of-function. This proposal investigates the therapeutic potential of dietary flavonoids-naturally occurring polyphenolic compounds with known antioxidant and neuroprotective properties, as small-molecule inhibitors that selectively recognize mismatches in r(CAG)n repeats. The central hypothesis is that specific flavonoids can destabilize toxic RNA secondary structures by binding selectively to A·A mismatches through hydrogen bonding, π-stacking, and/or base intercalation. 
The project will strengthen computational biophysics research at New Mexico Highlands University and provide training to undergraduate students from underrepresented groups. The findings will foster experimental collaborations across New Mexico’s academic institutions and inform novel therapeutic strategies for neurodegenerative diseases.