Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion

Figure 2

Potential mechanisms of C9orf72 hexanucleotide repeat expansion (HRE)-mediated neurodegeneration. Pathology due to repeats in C9orf72 gene may emerge from C9orf72 haploinsufficiency, RNA toxicity, and DPR accumulation. HRE in the noncoding region of the C9orf72 gene (1) form G-quadruplex structures (2). RNA transcribed from HRE DNA region can form different structures including G-quadruplexes (3) and RNA hairpins (4). HRE-containing RNA form RNA foci (5), which bind RNA-binding proteins. The last possible mechanism underlying pathology in C9FTD/ALS is through the repeat-associated non-ATG (RAN) translation, in which five different dipeptide repeat proteins can be formed—poly-GA, poly-GP, and poly-GR from the sense strand and poly-GP, poly-PA, and poly-PR from the antisense strand (6).