Fig. 2
From: Divergence, Convergence, and Therapeutic Implications: A Cell Biology Perspective of C9ORF72-ALS/FTD
Connections among functional defects downstream of repeat RNAs and DPRs. a G-quartets formed by repeat RNAs disrupt nucleocytoplasmic transport by sequestering RanGAP. It also promotes stress granule assembly. b DPRs induce stress granule assembly, which disrupts nucleocytoplasmic transport, inhibits global translation, and enhances RAN translation. Enhanced RAN translation produces more DPRs, forming a feedforward loop. c G-quartets formed by repeat RNAs disrupt nucleoli by sequestering NCL, whereas DPRs disrupt nucleoli by co-phase separating with NPM1 and NCL. In addition, DPRs cause DNA damage via NPM1 and nucleolar defects. d Repeat RNAs form R-loops, which causes DNA damage. e Cytoplasmic DPRs disrupt mitochondrial function, producing ROS that causes DNA damage. These discoveries not only provide us with an integrated view of C9ALS/FTD pathogenic mechanism but also help us better understand the fundamental biology underlying neurodegeneration.