Antibodies inhibit transmission and aggregation of <i>C9orf72</i> poly‐ <scp>GA</scp> dipeptide repeat proteins

Abstract

Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion <i>C9orf72</i>, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)_n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly-GA, poly-GP, and poly-PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly-GA induces nuclear RNA foci in (G4C2)₈₀-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly-GA and cerebellar extracts of <i>C9orf72</i> patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)₈₀ Treatment with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity of <i>C9orf72</i> brain extracts. Poly-GA-directed immunotherapy may thus reduce DPR aggregation and disease progression in <i>C9orf72</i> ALS/FTD.