Fig. 2

Pathogenesis of C9orf72 mutations. The GGGGCC HRE in the C9orf72 gene leads to production of toxic RNA. The RNA-binding protein HNRNPK, which can reverse the toxicity of sense and antisense repeat RNAs, undergoes mislocalization in the cytoplasm. RRM2, a downstream target of HNRNPK involved in DNA damage response, exhibits increased nuclear translocation but decreased expression in ALS.The GGGGCC HRE also leads to production of toxic proteins, including poly-GA, poly-GP, and to a lesser extent, poly-GR DPRs. These toxic proteins activate p53 target genes, exacerbating axonal degeneration and cell death. These proteins can also impair nucleocytoplasmic transport of proteins including TDP-43, by disrupting the function of RanGAP and NIR. Reduced expression of the C9orf72 gene leads to axonal transport defects, increased apoptosis, downregulation of HSP70 and HSP40, and dysfunction of the autophagy-lysosome pathway leading to accumulation of toxic proteins. Figure created with BioRender.com