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 arguments in favor of RAN-translation product toxicity derive primarily from work describing signs of cell death in the presence of non-AUG-originated proteins (14, 16) . Ranum et al. reported that cultured murine neuroblastoma cells transfected with SCA8 expanded CAG repeat constructs expressing polyGln, polyAla and polySer proteins triggered apoptosis, as shown by increased annexin-V staining (14) . Furthermore, the authors demonstrated the colocalization of caspase-8, an early indicator of apoptosis, with polyGln aggregates in the skeletal muscles of DM1 patients and in leukocytes from DM1 mice. Enhanced cell death was also observed in mammalian HEK293T cells transfected with G 4 C 2 constructs expressing polyProArg and polyGlyPro proteins (14) and in COS7 cells transfected with FXTAS CGG repeat plasmids expressing the polyGly protein (16) . Additionally, in a Drosophila model of FX-TAS, the presence of the RAN-translated polyGly protein was accompanied by rough-eye phenotype, which is a manifestation of toxicity in flies (16) .