Transthyretin promotes axon growth via regulation of microtubule dynamics and tubulin acetylation

Transthyretin (TTR), a plasma and cerebrospinal fluid protein, increases axon growth and organelle transport in sensory neurons. These TTR functions were suggested to underlie its activity in promoting nerve regeneration. While neurons extend their axons, the microtubule (MT) cytoskeleton is crucial for the segregation of functional compartments and axonal outgrowth. Herein, we investigated the hypothesis that TTR promotes axon elongation and regeneration by modulating MT dynamics. Indeed, we found that TTR KO mice have an intrinsic increase in dynamic MTs and reduced levels of acetylated α-tubulin in uninjured peripheral axons, and fail to modulate microtubule dynamics in response to sciatic nerve injury. Importantly, restoring acetylated α-tubulin levels of TTR KO DRG neurons using an HDAC6 inhibitor was sufficient to completely revert defective MT dynamics and neurite outgrowth. In summary, our results revealed a new role for TTR in the modulation of MT dynamics by regulating α-tubulin acetylation and support that this activity underlies TTR neuritogenic function.