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. 2023 Mar 16;17:1086895. doi: 10.3389/fncel.2023.1086895

FIGURE 2.

FIGURE 2

C9ORF72 loss and gain of function mechanisms impair autophagy. (A) Schematic illustration of the C9ORF72 gene. C9ORF72-ALS-FTD is characterized by a G4C2 hexanucleotide repeat expansion between exon 1a and exon 1b, which in patients can range up to thousands of repeats. (B) Haploinsufficiency of C9ORF72 gene causes the loss of function of the C9ORF72 protein by transcription inhibition. Given its importance in the initial steps of phagophore formation, reduction in the C9ORF72 protein impairs autophagy initiation, destabilizing WDR41 and SMCR8 complex. (C) Two pathological mechanisms involving the gain of function of the HRE gives rise to RAN translation and repeat-linked RNA mediated toxicity. In the case of RAN translation, the HRE can be translated in a sense or antisense manner giving rise to five different dipeptide repeats proteins (DPRs): PolyGA, PolyGP, PolyGR, PolyPR, and PolyPA. In the case of RNA-mediated toxicity the translated HRE can form higher order structures that sequester different RNA binding proteins, and thus forming RNA foci. The gain of function mechanisms can impair the autophagic flux and the formation of the autolysosome, leading to the accumulation of misfolded proteins.