Mechanism of normal and pathological stress granule formation. A) In normal, physiological conditions, neurons synthesize specialized proteins from capped transcripts. The proteins eIF4A, E and G complex to form the eIF4F pre-initiation complex, which interacts with the ribosome (40S) as well as other translational regulators to synthesize proteins. Association with the 60S ribosome complex allows protein synthesis to begin. B) Stress leads to phosphorylation of eIF2α, dissociation of ribosomes and many of the translation initiation factors, leaving mRNA bound eIF4G and poly-A binding protein. Nucleating RNA binding proteins bind the free RNA and also form protein/protein complexes, which initiate stress granule formation. Once initiated, other RNA binding proteins bind to the mRNA and to the nucleating RNA binding proteins to increase the size and complexity of SGs. These SGs are rapidly reversible upon removal of the stress, however prolonged SG formation affects cell biology by interacting with biological systems regulating apoptosis, signaling and RNA decay. C) Pathological proteins, such as TDP-43, FUS and tau, have a strong tendency to form oligomers, and then fibrils. The consolidation of RNA binding proteins during SG formation might promote oligomerization by creating cellular domains with higher concentrations of these proteins. Conversely, the increased stability of oligomers and fibrils might serve as a nidus for SG formation, leading to over-active SG formation. Microtubule associated protein tau also participates in this process because it mislocates to the soma and dendritic arbor leading to interactions with SG proteins and potentially stimulating SG formation . Tau also directly binds RNA .