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Non-enzymatic Activity of the α-Tubulin Acetyltransferase αTAT Limits Synaptic Bouton Growth in Neurons.
Current Biology ( IF 9.2 ) Pub Date : 2020-01-09 , DOI: 10.1016/j.cub.2019.12.022
Courtney E Coombes 1 , Harriet A J Saunders 2 , Anirudh G Mannava 1 , Dena M Johnson-Schlitz 3 , Taylor A Reid 1 , Sneha Parmar 1 , Mark McClellan 1 , Connie Yan 4 , Stephen L Rogers 5 , Jay Z Parrish 4 , Michael Wagenbach 6 , Linda Wordeman 6 , Jill Wildonger 3 , Melissa K Gardner 1
Affiliation  

Neuronal axons terminate as synaptic boutons that form stable yet plastic connections with their targets. Synaptic bouton development relies on an underlying network of both long-lived and dynamic microtubules that provide structural stability for the boutons while also allowing for their growth and remodeling. However, a molecular-scale mechanism that explains how neurons appropriately balance these two microtubule populations remains a mystery. We hypothesized that α-tubulin acetyltransferase (αTAT), which both stabilizes long-lived microtubules against mechanical stress via acetylation and has been implicated in promoting microtubule dynamics, could play a role in this process. Using the Drosophila neuromuscular junction as a model, we found that non-enzymatic dαTAT activity limits the growth of synaptic boutons by affecting dynamic, but not stable, microtubules. Loss of dαTAT results in the formation of ectopic boutons. These ectopic boutons can be similarly suppressed by resupplying enzyme-inactive dαTAT or by treatment with a low concentration of the microtubule-targeting agent vinblastine, which acts to suppress microtubule dynamics. Biophysical reconstitution experiments revealed that non-enzymatic αTAT1 activity destabilizes dynamic microtubules but does not substantially impact the stability of long-lived microtubules. Further, during microtubule growth, non-enzymatic αTAT1 activity results in increasingly extended tip structures, consistent with an increased rate of acceleration of catastrophe frequency with microtubule age, perhaps via tip structure remodeling. Through these mechanisms, αTAT enriches for stable microtubules at the expense of dynamic ones. We propose that the specific suppression of dynamic microtubules by non-enzymatic αTAT activity regulates the remodeling of microtubule networks during synaptic bouton development.

中文翻译:

α-Tubulin乙酰转移酶αTAT的非酶活性限制了神经元中突触Bouton的生长。

神经元轴突终止为突触钮扣,与靶标形成稳定但可塑性的连接。突触钮扣的发育依赖于长寿和动态微管的基础网络,这些网络为钮扣提供结构稳定性,同时也允许其生长和重塑。然而,解释神经元如何适当平衡这两个微管种群的分子尺度机制仍然是一个谜。我们假设,α-微管蛋白乙酰转移酶(αTAT)既可以稳定长寿命的微管通过乙酰化抵抗机械应力,又与促进微管动力学有关,可能在此过程中起作用。使用果蝇神经肌肉接头作为模型,我们发现非酶促dαTAT活性会通过影响动态,但不稳定,微管。dαTAT的损失导致异位钮扣的形成。通过重新补充无酶活性的dαTAT或用低浓度的微管靶向剂长春碱处理,可以抑制这些异位钮扣,这种作用可抑制微管动力学。生物物理重建实验表明,非酶促αTAT1活性会破坏动态微管的稳定性,但不会实质性地影响长寿命微管的稳定性。此外,在微管生长过程中,非酶促αTAT1活性会导致末端结构不断延长,这可能是由于末端结构重塑,随着微管年龄的增加,突变频率的加速度增加了。通过这些机制,αTAT以动态微管为代价富集了稳定的微管。
更新日期:2020-01-09
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