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.

Cellular inclusions containing RAN-translation products are present in tissues that are affected in SCA8, DM1, FXTAS and ALS/FTD. In SCA8, the most abundant polyAla was found to form inclusions in the remaining Purkinje cells in human autopsy samples, whereas in the mouse disease model, the inclusions were found throughout the cerebellum in dendrites and in Purkinje cells, as detected by immunostaining with antibodies to the putative SCA8-polyAla protein (14) . In DM1, inclusions of RANtranslation products formed nuclear polyGln aggregates that are detected in patients' blood at higher frequency than in myoblasts and skeletal muscle; in DM1 transgenic mice, such inclusions are more abundant in leukocytes than in cardiac myocytes (14) . In FXTAS patients, RAN-translated products were found to form Gly-positive inclusions that accumulate in the hippocampus, cerebellum and cortex, whereas in a mouse model of the disease, polyGly aggregated in the hypothalamus, cortex and brainstem (16) . Interestingly, in FXTAS, these inclusions were ubiquitinpositive. Although in SCA8 and DM1, only the most expressed RAN-translation products were found to aggregate, in C9ALS/FTD, all possible DRPs from either sense or antisense transcripts have been detected in inclusions that exhibit dot-like and star-like shapes (Supplementary Table S2 ). DPRs were present in the patient tissues and in cells of C9ALS/FTD experimental models and were restricted to neurons, being highly abundant in neocortical regions, the cerebellum and the hippocampus, more variable in the striatum and substantia nigra and rare or absent in the medulla and spinal cord (15, (17) (18) (19) 22, (31) (32) (33) 36, 37) . These aggregates colocalize with inclusions that are positive for p62 and negative for phospho-TDP-43, a classical molecular feature of C9ORF72 mutation carriers (19, 22, 32) .