Fig. 3.

Maturation of physiological SGs into pathogenic aggregates is mainly driven by chronic stress and mutant RBPs and/or RNA repeats, with progressive impairment of their physiological clearance. Stress mediated assembly of untranslating mRNPs into microscopic canonical, dynamic and less stable SGs is assisted by RNA and RBPs. Specific stress conditions result in the formation of non-canonical cytotoxic SG subtypes. Genetic mutations in LCDs/IDPRs/ RNA-binding motifs of RBPs (TDP-43, FUS, EWS, Ataxins, hnRNPA1, hnRNPA2/B1TAF15 and TIA-1/R; see Table 1) and/or their post-translational modifications (PTMs) further shift maturation of SGs into non-canonical, less dynamic and cytotoxic SG subtypes. Further, clearance of these SGs is reduced by inhibition of autophagy and/or mutation in the autophagy associated factor VCP (valosin-containing protein). Chronic localization of disease-linked defective RBPs, ALS/FTD-associated dipeptide repeats (DPRs) and components of sequestosome (e.g. sequestosome protein 1 or p62/SQSTM1) promote transition to insoluble, more fibrillar and persistent pathological SGs. Points of therapeutic interventions (shown in red) target SG assembly, maturation and clearance. ASO anti-sense oligo(s), KD knock-down