FIGURE 7.

TDP-43 aggregation model through the RRM2 intermediate state. For simplicity, TDP-43 is represented with two circles for the RRM domains (black, RRM1; red, RRM2) and black lines for the disordered N and C terminus. TDP-43 can interact with other protein partners to form functional complexes represented by a green circle. An equilibrium exists where a small percentage of RRM2 can populate its intermediate state (RRM2 conversion from red circle to red square) but remain in functional complexes. Disease triggers (lightning bolt) can result in loss of RNA binding (dashed blue line), protein-protein interactions, or cleavage (removal of RRM1 and N terminus) that produces misfolded states (dashed boxes) where the population of the RRM2 intermediate increases. These misfolded states can result in dysfunctional complexes by aberrant protein-protein interactions (spiked green circle) or aggregates with other proteins (overlaid TDP-43 molecules). These disease states reduce the available pool of functional TDP-43 and lead to the propagation of ALS and FTLD.