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.

Several mechanisms of translation initiation are possible; however, none seems to explain RAN translation. The cap-dependent scanning mechanism and cap-independent internal ribosome entry site (IRES) mechanisms are the best known types of translation initiation (23, 24) ; however, other initiation mechanisms such as leaky scanning, ribosome shunting or reinitiation are also known (25) . The fact that microsatellite expansions do not follow the canonical rules of translation initiation and generate series of homopolymeric or dipeptide repeat proteins (DPRs) in multiple frames indicates the involvement of a novel yet unrecognized process or the altered utilization of known processes. RNA structures formed by the repeats must be considered when deciphering mechanisms of RAN translation because their formation and stability have been shown to affect the abundance of RAN translation products (14) . Could such structures be used to trigger an IRES type of mechanism? Could IRES translation-associated factors (ITAFs) that normally help to stabilize RNA structures be more abundant at repeat-formed structures, allowing translation initiation without an AUG start codon? Could alternative start codons occurring within or in close proximity to these repeats permit the noncanonical initiation of protein production? These questions and many others arise when dissecting the novel ambiguity of expanded repeats.