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. 2020 Oct 20;64(5):847–861. doi: 10.1042/EBC20200002

Figure 5. DDR defects in ALS with C9orf72 mutations.

Figure 5

G4C2–NREs in the first intron of the C9ORF72 gene increases RRE, which impairs DDR through binding to RNA-binding proteins. Transcription over G4C2–NREs leads to R-loop formation and subsequent DNA damage accumulation. RAN translation produced DPRs that can increase ROS, induce nuclear membrane alterations (NMA) and may potentially sequester DDR proteins. NMA include structural and functional disturbances at the nuclear pore complexes (NPC) involving transport receptors. Abnormal nucleo-cytoplasmic transport of both RNA and proteins at NPC has been suggested to be, either related to molecule sequestrations by DPR and RRE or in parallel with other factors, a strong C9ORF72 disease modifier. G4C2–NREs also decreases C9ORF72 expression, which impairs autophagy and exacerbates DPRs accumulation. Mutated genes identified in ALS (red), homologous recombination (HR; green) and autophagy (brown). Dotted arrows are proposed, yet not completely proven, interactions.