Dementia Japan 36:473-485, 2022

Frontotemporal lobar degeneration due to C9orf72 repeat expansion mutation : from molecular pathogenesis toward therapy development

Kohji Mori

Psychiatry, Osaka University Graduate School of Medicine

The C9orf72 repeat expansion mutation is a common genetic cause of familial FTLD and ALS.　The pathogenesis of C9orf72 FTLD/ALS could be based on acquired toxicity from bidirectionally transcribed repeat RNAs and dipeptide repeat proteins (DPRs) produced by RAN translation, which is enhanced by haploinsufficiency of the C9ORF72 protein.　Various RNA-binding proteins, stress-related factors, and protein and/or RNA-degrading enzymes may modulate the pathogenesis.　Promotion of repeat RNA degradation, inhibition of repeat RNA transcription, and inhibition of DPR production are all considered as potential therapeutic targets.　Moreover, DPR can be measured in cerebrospinal fluid and is used as a biomarker to demonstrate the proof of concept for drug discovery.

Address correspondence to Dr. Kohji Mori, Psychiatry, Osaka University Graduate School of Medicine (2-2 Yamadaoka, Suita, Osaka 565-0871, Japan)