Fig. 3

Overview of how translation regulation is affected by ALS-related genes. (A) The impact of ALS-related genes on translation initiation. Integrated stresses, which are frequently observed in ALS, induce eIF2α phosphorylation, leading to the sequestration of eIF2B and impairment of translation initiation. Poly-GR/PR and TDP-43 may result in the sequestration of translation factors, thereby affecting translation initiation. Poly-GR/PR can also bind to the polypeptide exit tunnel of the ribosome thus blocking translation initiation. (B) The influence of ALS-related genes on translation elongation. poly-GR/PR can bind to the polypeptide exit tunnel of the ribosome and inhibit translation elongation. Another important process for translation elongation is the charge of tRNAs with cognate amino acids by aminoacyl-tRNA synthetases. Under stress conditions, ANG may translocate to cytoplasm and cleave tRNAs which further inhibits translation. (C) When ribosome stalling occurs, ribosome quality control (RQC) pathway is activated to split the stalled ribosome subunits. NEMF participates in the recognition of obstructed large ribosomal subunit and recruits LTN1 E3 ligase to catalyze the poly-ubiquitination of the nascent peptide chain for degradation. NEMF also can add C-terminal tails to the nascent chains to facilitate its ubiquitination. NEMF and LTN1 mutations disrupt RQC pathway and cause ALS-like phenotypes in mice. As poly-GR/PR can bind to the polypeptide exit tunnel of the ribosome, they may cause ribosome stalling and trigger RQC pathway. (D) Under stress conditions, RBPs and mRNAs undergo LLPS (liquid-liquid phase separation) to form membrane-less condensates which are termed stress granules. The assembly and disassembly of stress granules are dynamic in response to stress stimuli. However, ALS-related mutations in many genes and poly-GR/PR influence the dynamics of stress granule formation and promote the transition of stress granules to solid-like condensates which may influence global translation by sequestering translation machinery. (E) ALS-related mutations in FUS and TDP-43 have been shown to impair localized translation in neurites