Fig. 2

Main mechanisms associated with polyG diseases. A CGG repeats are triplet nucleotides located in non-coding regions. There are two main pathogenesis mechanisms of non-coding CGG expansion related diseases. Mild and moderate CGG repeats can translate into polyglycine, and the protein toxicity causes neurodegeneration disorders, including FXTAS and NIID. In contrast, a high degree of repeated CGG sequences will lead to CpG island hypermethylation. Hypermethylation of CpG can lead to transcriptional gene silencing, resulting in partial or complete loss of the native protein encoded by the gene, resulting in abnormal FXS or asymptomatic NIID. B Hypotheses for the mechanism of nuclear inclusion body formation. CGG repeat RNAs can fold into complex structures, including hairpins, which aberrantly interact with and sequester RBPs into RNA foci. Non-coding RNA repeats could undergo canonical ribosome-dependent translation mechanism, thereby producing toxic polyG peptides. C Possible therapeutic approaches for polyG diseases. ASOs can bind to mRNA that contains pathological repeat expansions, inducing degradation of the target RNA. Small molecules can interact with mutant mRNA and break the hairpin structure. CRISPR/Cas9 technology can be used to excise portions of CGG repeats to inhibit methylation or translation of toxic proteins