Huntington’s
disease (HD) is a genetic disorder caused by
a CAG expansion mutation in the huntingtin gene leading
to polyglutamine (polyQ) expansion in the N-terminal part of huntingtin
(Httex1). Expanded polyQ, through a complex aggregation pathway, forms
aggregates in neurons and presents a potential therapeutic target.
Here we show Httex1 aggregation suppression by arginine and arginine
ethyl ester (AEE) in vitro, as well as in yeast and
mammalian cell models of HD, bearing expanded polyQ. These molecules
also rescue locomotion dysfunction in HD Drosophila model. Both molecules alter the hydrogen bonding network of polyQ
to enhance its aqueous solubility and delay aggregation. AEE shows
direct binding with the NT17 part of Httex1 to induce structural
changes to impart an enhanced inhibitory effect. This study provides
a platform for the development of better arginine based therapeutic
molecules against polyQ-rich Httex1 aggregation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.