Figure 4.

Multiple ALS genes indicate disturbances of RNA-binding proteins and RNA synthesis, trafficking, and function. A diversity of pathologies may arise including altered histone acetylation (elongator acetyltransferase complex subunit 3 [ELP3]), disturbed helicase activity (senataxin), altered splicing and synthesis of microRNA (TAR DNA-binding protein [TDP-43], fused in sarcoma [FUS]), deposition of RNA foci and generation of RNA dipeptides (C9orf72), impaired nucleocytoplasmic transport (C9orf72), and formation of aggregates via stress granules (many of the RNA-binding proteins). Axonal movement of RNA granules may be impaired, with secondary alterations in local protein translation in dendrites and neuromuscular junctions.