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.

Frameshifted polyAla proteins apparently add to polyGln toxicity in cells with expanded CAG repeats. In contrast to the slow, progressive accumulation that has been detected for CAG/Gln constructs, transfection with GCA/Ala constructs results in an early and rapid accumulation of Ala-containing products and a more severe phenotype. The presence of a transgene expressing the polyAla tract without the context of the ataxin-3 protein is sufficient for aggregate formation, which produces a toxic phenotype. It has been shown that (−1) frameshifting events and the concomitant production of polyAla-containing ataxin-3 are key factors that contribute to toxic eye phenotype development, as observed in the Drosophila model of SCA3. The in vivo expression of the polyGln-containing ataxin-3 alone was not sufficient to cause a degenerative phenotype in the fly (28) .