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.

As discussed in this review, mounting evidence demonstrates that simple repeat expansions causing several human neurological diseases trigger noncanonical translation initiation and elongation, and two unusual processes, RAN translation and frameshifting, are recognized across the repeats. Protein products of RAN translation and frameshifting were detected in patient tissues and in mouse and Drosophila models of the disorders in addition to numerous human cell lines after transfection with specific constructs. However, the methods used to study these processes and detect their products have limitations that give raise to concerns and further questions. For example, it cannot be excluded that some antibodies used to detect specific RAN translation or frameshifting products may recognize both entities. Thus, the results obtained with commonly used immunological methods need to be confirmed by other methods such as MS. Strong promoters used in genetic constructs may explain the higher frequency of frameshifting observed in cellular models compared with patient tissues as well as detection of RAN translation and frameshifting products in disease models expressing nonpathological numbers of repeats.