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.

Two years after the first report on RAN translation, Todd et al. showed that this noncanonical protein synthesis also occurs at CGG repeats in FXTAS (16) . Non-AUG-initiated proteins were found in transfected mammalian cells (Supplementary Table S1 and Figure S1 ), in patients' brain tissues and in different FXTAS model organisms, including transgenic mice and flies (Supplementary Table S2 ). Homoaminoacid RAN translation proteins were expressed in two of three possible reading frames: polyglycine (polyGly) from the GGC repeat frame and polyAla from the GCG frame, while no polyarginine (polyArg) was detected from the reading frame with CGG repeats. Different abundances of these proteins, i.e. predominance of polyGly and an inability to detect polyArg, may reflect a large difference in the initiation frequency in different frames, preferential dropoff of nascent polyArg peptide or alternatively, large differences in cellular stability of polypeptides that were synthesized in different frames.