Figure 2.

RQC defects in FTD and ALS and their link with ribosome stalling. (A) The E3 ubiquitin ligase ZNF598 co-translationally regulates the expression of the peptide chain derived from the G₄C₂ repeat expansion in C9orf72 gene, by directing the aberrant peptides to the proteasome system and suppressing the caspase-3-mediated apoptotic pathway. However, the ZNF598R69C mutant observed in pathologic conditions showed a loss of these functions, resulting in translation inhibition. (B) In an ALS context, pathology-correlated mutants R521G and P525L of FUS have a higher cytoplasmic residency and can highly associate with translating ribosomes [42]. Upon mTORC2 inhibition, enhanced FUS association with polyribosomes results in the inhibition of global translation (see text for details).