We performed a genetic screen for regulators of RAN translation and identified small ribosomal protein subunit 25 (RPS25), presenting a potential therapeutic target for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia and other neurodegenerative diseases caused by nucleotide repeat expansions.
RAN proteins have been reported in a growing number of diseases, including spinocerebellar ataxia type 8 (SCA8), myotonic dystrophy type 1 (DM1), Fragile-X tremor ataxia syndrome (FXTAS), and C9ORF72 amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD).
Additionally, these findings suggest the need to test therapeutic strategies that target both sense and antisense RNAs and RAN proteins in C9ORF72 ALS/FTD, and to more broadly consider the role of antisense expression and RAN translation across microsatellite expansion diseases.
Given that both foci formation and RAN translation in c9FTD/ALS require the synthesis of GGGGCCexp RNA, therapeutic strategies that target these transcripts and result in their neutralization or degradation could effectively block these two potential pathogenic mechanisms and provide a much needed treatment for c9FTD/ALS.