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.

Over the past several years, these traditional paradigms of repeat toxicity have been reevaluated, as bidirectional transcription through repeat regions of genes associated with numerous human neurological disorders has been described (12, 13) along with non-AUG translation initiation at expanded CAG, CGG and GGGGCC (G 4 C 2 ) repeats (14) (15) (16) (17) (18) (19) (20) (21) (22) . The discovery of repeat-associated non-AUG (RAN) translation, which indicates that noncoding diseases could involve unexplored yet toxic proteins and that coding diseases are likely to produce unexpected proteins in other frames, has proven how inscrutable these diseases remain. Importantly, novel proteins have been found to accumulate in the relevant tissues of the diseases in both patients and model organisms, suggesting that homopolymeric or dipeptide repeat repeat-associated non-AUG (RAN) translation products might play a role in microsatellite expansion disorders. Nevertheless, their precise contribution to the process of pathogenesis of SCA8, DM1, FXTAS and C9ALS/FTD remains to be determined.