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.

The frequency of frameshifting along the expanded CAG tract of ATXN3 and HTT is dependent on repeat length, and the formation of intranuclear inclusions containing frameshifted proteins increases with the number of repeats (26, 27, 30) . In SCA3 patients, protein aggregates were observed with ≥75 CAGs, whereas in transfected COS7 cells, they were abundant after protein expression from a construct containing 82 CAGs and rare from a construct containing at 37 CAGs. In the case of the shortest constructs, with 14 CAGs, whether frameshifting products were observed depended on the detection method (Supplementary Table S3 and Figure S3 ) (27) . Interestingly, not all polyGlnpositive cells contained frameshifted proteins; however, the frequency of such cells increased dramatically as the CAG repeat length increased (26) . Flanking sequences do not influence frameshifting within the mutant ATXN3 transcript (27) .