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.

The discovery of RAN translation may challenge the common dogma that the toxicity of noncoding repeat disorders is exclusively caused by mutant transcripts. What are the arguments indicating that RAN-translated products are relevant or irrelevant to neurodegeneration? The majority of data against the toxicity of RAN proteins originate from work on C9ALS/FTD. First, no correlation between the neuroanatomical distribution of DPR inclusions and the degree of degeneration in different regions of the central nervous system in C9ALS/FTD was reported (32) , and tissues containing DPRs showed no signs of cell loss or other apparent symptoms of neurodegeneration (31) . Second, RAN translation-related pathology was less frequently detected or absent in lower motor neurons in the spinal cord, the area affected in ALS (15, 22, 32) . However, as suggested, this result may be a consequence of increased cell death and atrophy in this region, resulting in a reduced number of cells available for analysis. Additionally, the levels of RAN-translated proteins and their capacity to form aggregates may be lower in the spinal cord (15), or even not observed in iPSC-derived motor neurons (38) . Third, despite the outstay of RAN-translated proteins, the toxic phenotype of human C9ORF72 iPSC-derived neurons was rescued upon antisense oligonucleotide (ASO) treatment (20) . As reported by Donnelly et al., treatment of these cells with ASO efficiently abrogated known pathogenic features of C9ALS/FTD, such as intranuclear G 4 C 2 repeat RNA foci formation, ADARB2 protein sequestration, deregulated gene expression and susceptibility to glutamate toxicity; however, this treatment did not affect the level of the polyGlyPro dipeptide.