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.

A decade before RAN translation was discovered, Rouleau et al. proposed that frameshifting within expanded CAG repeats of the ATXN3 gene resulted in the production of a polyAla-containing protein, which forms intranuclear inclusions contributing to toxicity (27) . Six years later Davies and Rubinsztein demonstrated that this phenomenon is not restricted to SCA3 and occurs also in translation of the HTT gene, which is responsible for HD (29) . Frameshifting one nucleotide downstream ((−1) frame) or one nucleotide upstream ((+1) frame) during translation results in the generation of a new protein, and in addition to the polyGln encoded by the (0) CAG frame, the polyAla and polySer proteins can be produced from the (−1) GCA frame and the (+1) AGC frame, respectively. Do they add novel toxic elements to the established toxicity of the expanded polyGln proteins, thus participating in polyGln disorder pathogenesis? What is the role of CAG repeats in the mechanism of ribosomal frameshifting? These and other emerging questions are addressed in this chapter.