Fig. 2

Proposed mechanisms of TDP-43 accumulation in axons. Illustration of motor units with the various possibilities for formation and accumulation of pathological TDP-43 in axons. A Alterations in axonal transport may result in a shift towards more anterograde or less retrograde transport of TDP-43 which will subsequently modify its local concentrations in axons and synapses. B TDP-43 spreading via extracellular vesicles. One way by which TDP-43 is disposed from cells is via extracellular vesicles. These TDP-43-containing vesicles could be removed from Schwann cells or skeletal muscles and be taken-up into neighboring axons, which cannot sustain protein overloads, and are less equipped with the appropriate machinery to cope with protein accumulation. C Alterations in proteostasis equilibrium driven by either non-regulated synthesis of TDP-43 in axons, or as been shown, by dysfunction in the process of TDP-43 proteolysis and clearance from axons due to its phosphorylated state