Figure 8.

Model of futsch mRNA regulation by TDP-43. A, In controls, TDP-43 transports futsch mRNA to synapses where translation occurs, resulting in stabilized synaptic connections. B, In the ALS model, TDP-43 alters the localization of futsch mRNA, increasing its concentration in the cell body and reducing its concentration at the NMJ. Additionally, TDP-43 negatively regulates Futsch expression post-transcriptionally at the level of translation, resulting in decreased Futsch protein levels in both the cell body and at the NMJ relative to mRNA concentrations. Subsequently, this leads to decreased microtubule stability, increased aggregation of TDP-43, and reduced NMJ size, locomotor function, and life span. C, After Futsch overexpression in the context of TDP-43, futsch mRNA localization and Futsch protein levels are restored subsequently, resulting in a rescue of microtubule stability, TDP-43 solubility, as well as NMJ size, locomotor function, and life span.