Eira Jessica, Magalhães Joana, Macedo Nídia, Pero Maria Elena, Misgeld Thomas, Sousa Mónica M, Bartolini Francesca, Liz Márcia A
ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
Neurodegeneration Team, Nerve Regeneration Group, Instituto de Biologia Molecular e Celular-IBMC, and i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
Front Cell Dev Biol. 2021 Nov 8;9:747699. doi: 10.3389/fcell.2021.747699. eCollection 2021.
Transthyretin (TTR), a plasma and cerebrospinal fluid protein, increases axon growth and organelle transport in sensory neurons. While neurons extend their axons, the microtubule (MT) cytoskeleton is crucial for the segregation of functional compartments and axonal outgrowth. Herein, we investigated whether TTR promotes axon elongation by modulating MT dynamics. We found that TTR KO mice have an intrinsic increase in dynamic MTs and reduced levels of acetylated α-tubulin in peripheral axons. In addition, they failed to modulate MT dynamics in response to sciatic nerve injury, leading to decreased regenerative capacity. Importantly, restoring acetylated α-tubulin levels of TTR KO dorsal root ganglia (DRG) neurons using an HDAC6 inhibitor is sufficient to completely revert defective MT dynamics and neurite outgrowth. In summary, our results reveal a new role for TTR in the modulation of MT dynamics by regulating α-tubulin acetylation modulation of the acetylase ATAT1, and suggest that this activity underlies TTR neuritogenic function.
转甲状腺素蛋白（TTR）是一种血浆和脑脊液蛋白，可促进感觉神经元的轴突生长和细胞器运输。当神经元延伸其轴突时，微管（MT）细胞骨架对于功能区室的分离和轴突生长至关重要。在此，我们研究了TTR是否通过调节MT动力学来促进轴突伸长。我们发现，TTR基因敲除小鼠外周轴突中动态MT的固有增加以及乙酰化α-微管蛋白水平的降低。此外，它们在坐骨神经损伤后无法调节MT动力学，导致再生能力下降。重要的是，使用HDAC6抑制剂恢复TTR基因敲除背根神经节（DRG）神经元的乙酰化α-微管蛋白水平足以完全恢复有缺陷的MT动力学和神经突生长。总之，我们的结果揭示了TTR在通过调节α-微管蛋白乙酰化来调节MT动力学中的新作用，调节乙酰化酶ATAT1，并表明这种活性是TTR神经突生成功能的基础。
