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.

What is the role of the frameshifted species generated in SCA3 and HD, and are they relevant to the pathogenesis of these diseases? Previously, both polySer-and polyAlacontaining proteins were shown to be modifiers of mutant huntingtin toxicity (79) . It was also proposed that translational frameshifting within expanded CAG stretches may contribute to the observed variations in HD course and onset, leading to cell-selective neurotoxicity on both the cellular and organismal levels. This phenomenon could at least partially account for the degeneration of selective neuronal populations in patients, although the disease-related polyQ proteins are widely expressed. Furthermore, tissue-specific variations in polyQ length may contribute to cell-selective pathogenesis because the CAG stretch is several repeats longer in the brain than in other tissues even within a single individual (80, 81) , and the frequency of frameshifting increases with repeat length. Taken together, frameshifted proteins are important factors that contribute to polyGln aggregate toxicity.