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.

Recently, new experimental evidence on the mechanism of frameshifting at expanded CAG repeats has been published (30) . The formation of various transframe-encoded species generated via frameshifting at long CAG repeats in HD is proposed to be a consequence of a depletion of the charged glutaminyl-transfer RNA tRNAGln-CUG that pairs exclusively with the CAG codons. It has been shown that the amount of tRNAGln decreases with increasing length of the encoded CAG sequences (hungry codons), and in N2A cells expressing 65 or 103 CAG repeats, a significant increase in the frequency of frameshifting was observed from, respectively, 60 to 80%. Moreover, the frameshifting frequency varies among different cell lines. In N2a cells and HeLa cells, which differ in their intrinsic concentration of tRNAGln-CUG, the higher frameshifting frequency occurs in the N2a cells, which have a lower amount of tRNAGln-CUG than the HeLa cell line (Supplementary Table S3 ). Interestingly, the concentration of tRNAGln-CUG also differs among different brain areas, and as shown in HD mice, the tRNAGln-CUG concentration is lower in the striatal and hippocampal tissues than in the cortical and cerebellar regions (30) . This fact raises the interesting question of whether tRNAGln-CUG levels also vary among different brain tissues in HD patients, thus contributing to the cellselective pathology of the disease. Because the most prominent early effects in HD have been observed in the striatum, even though striatal neurons do not selectively express higher levels of HTT mRNA (105) , this possibility could provide a mechanistic explanation of the selective pathology and importantly disclose a new therapeutic target. However, this issue remains to be examined. The mechanism of frameshifting in SCA3 and HD seems to be more similar to viral −1 PRF since mostly polyAlacontaining proteins are generated. However, we cannot exclude +1 PRF events, as observed in Escherichia coli and yeasts (106) (107) (108) , because polySer-containing proteins were detected in HD (29) . The +1 PRF is also enhanced by the presence of 'hungry codons' in the A site (109, 110) . This information would support the idea suggesting that depletion of cognate charged tRNAGln-CUG is a cause of frameshifting within Htt transcript, however polySer proteins resulting from +1 frameshifting were much rarely detected in this study (30) .