Chapter 10 - Inhibition of Aggregation of Mutant Huntingtin by Nucleic Acid Aptamers In Vitro and in a Yeast Model of Huntington’s Disease

Abstract

Huntington’s disease (HD) is caused by elongation of the polyglutamine (polyQ) tract at the N-terminus of a protein called huntingtin. Elongation of the polyglutamine tract causes protein aggregation that has been linked to disease progression. Aptamers are relatively short, RNA/DNA sequences which bind to their target molecules with high specificity and affinity. This may inhibit protein unfolding or protein–protein interaction, the first step(s) in protein aggregation. Aptamers were selected against the elongated polyQ stretch of mutant huntingtin and reduced its aggregation. This resulted in decrease in membrane porosity and oxidative stress in RBCs and rescue of sequestration of essential proteins in vitro. When expressed in a yeast HD model, the aptamers led to decreased protein aggregation which corresponded with reduced oxidative stress, rescue of endocytotic defects, and increased cell viability. As almost all protein misfolding diseases are associated with aggregation of the diseased protein following the nucleation mode of fibrillation, aptamers may provide a promising route to designing a therapeutic strategy for such disorders.