No abstract

Proteomics and neuropathological validation show that aberrant poly-GR/PR proteins in C9orf72 ALS/FTD bind STAU2 and ribosomes and inhibit translation.

Highlights d Importins directly bind to arginine-rich dipeptide repeat proteins (R-rich DPRs) d R-rich DPRs induce importin and TDP-43 condensation d Poly-GR impairs TDP-43 nuclear import d Elevated importin levels shield R-rich DPRs from pathological interactions

The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non-canonical translation of the expanded repeat results in abundant poly-GA inclusion pathology throughout the CNS. (GA) 149 -CFP expression in mice triggers motor deficits and neuroinflammation. Since poly-GA is transmitted between cells, we investigated the therapeutic potential of anti-GA antibodies by vaccinating (GA) 149 -CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin-(GA) 10 conjugates and pre-aggregated carrier-free (GA) 15 . Only ovalbumin-(GA) 10 immunization induced a strong anti-GA response. The resulting antisera detected poly-GA aggregates in cell culture and patient tissue. Ovalbumin-(GA) 10 immunization largely rescued the motor function in (GA) 149 -CFP transgenic mice and reduced poly-GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin-(GA) 10 -immunized poly-GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/ macrophages. Moreover, cytoplasmic TDP-43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers.