The paper reports that a single deuterium-for-hydrogen substitution within the CAG repeat tract of ATXN2 stabilizes the repeat by reducing secondary-structure formation, and that CAA interruptions produce a similar but weaker stabilizing effect.

ATXN2 CAG expansions are implicated in neurodegenerative risk including parkinsonism, so identifying intrinsic stabilizers of repeat expansion advances mechanistic understanding and potential genetic-risk modulation strategies, but the D/H isotope approach is unlikely to be directly translatable as…

CAG repeats in the first exon of the ATXN2 gene play a key role in the development of a number of neurodegenerative diseases. Understanding the mechanisms underlying CAG tract expansions and the factors influencing them could lead to the development of new methods for the prevention and treatment of these diseases. It was established that a single D/H substitution of a hydrogen bond in the CAG tract increases its stability, thereby reducing the likelihood of formation of secondary structures that interfere with the reading of genetic information from the glutamine-coding region. CAA interruptions in the CAG tract in specific locations can have a similar, but weaker, stabilizing effect.