RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders

Wojciechowska, Marzena; Olejniczak, Marta; Galka-Marciniak, Paulina; Jazurek, Magdalena; Krzyzosiak, Wlodzimierz J.

Microsatellite repeat expansions have also been demonstrated to affect the maintenance of a reading frame by challenging the translation elongation machinery. Frameshifting by one nucleotide downstream or one nucleotide upstream during translation across elongated CAG repeats of ATXN3 and HTT transcripts results in the generation of new proteins containing polyAla (SCA3 and HD) and pol-ySer (HD) (26) (27) (28) (29) (30) . Such ribosome slippage occurs probably at random positions along the expanded CAG repeats in tissues and cells, and what initiates the process remains unknown. Nonetheless, the frequency of frameshifting increases with the number of CAG repeats and seems to depend on the formation of hairpin structures by the repeats. The resulting chimeric mutant proteins accumulate in intranuclear and cytoplasmic aggregates that are toxic on the cellular level, thus contributing to the pathogenesis of SCA3 and HD (26, 28, 30) .