Fig. 3

Proposed pathological mechanism of TDP-43 in axons/NMJs. Recent evidence on both the biological and pathological roles of axonal TDP-43 imply that TDP-43 accumulates in remote axons and presynaptic compartments of motor neurons and forms pTDP-43 condensates. Those structures sequester mRNAs critical for local synthesis of mitochondrial and ribosomal proteins. The disruption in local protein synthesis of these initiates a vicious cycle between mitochondria dysfunction, generation of Reactive Oxygen Species (ROS), and further impairment of local protein synthesis. This specifically impacts the NMJ due to the strict dependency of the NMJ on those processes, thus facilitating NMJ and axon degeneration