MICROTUBULE POST-TRANSLATIONAL MODIFICATIONS IN AXON REGENERATION

描述(由申请人提供)：缺乏强大的轴突再生是中枢神经系统(CNS)内神经元损伤后神经功能恢复的主要障碍之一。相比之下，外周神经系统(PNS)中的神经元在损伤后具有显著的再生能力。轴突再生的程度不仅取决于环境中抑制性线索的存在，还取决于受损神经元的内在生长能力。事实上，仅阻断细胞外抑制影响并不足以实现完整的轴突再生，强调需要更好地了解控制受损神经元内在再生能力的机制。支配轴突再生的机制既在细胞体中运作，也在轴突局部运作。局部轴突反应允许受损神经元向细胞体发回信号，并将受损的轴突尖端转变为新的生长锥状结构，这两个过程对于启动再生至关重要。在继续我们的轴突对损伤的反应的研究中，我们最近专注于微管(MT)细胞骨架。我们发现组蛋白脱乙酰酶HDAC5是一种新的损伤调节型微管蛋白脱乙酰酶，控制轴突再生。HDAC5在损伤的三叉神经节顶端聚集并去乙酰化微管蛋白，而不是中枢神经轴突。HDAC5介导的微管蛋白去乙酰化对三叉神经节神经元的再生能力是必不可少的，但在中枢神经系统神经元中不能发生。除了微管蛋白去乙酰化，我们观察到三叉神经节细胞轴突损伤也增加了微管蛋白酪氨酸化。已知微管蛋白乙酰化和酪氨酸化有助于MTS的动力学性质和MT依赖的轴突运输。然而，由损伤引发的调节MT翻译后修饰的信号通路以及这些修饰在轴突再生中所起的确切作用仍然不清楚。在这里，我们建议揭示MT在受损轴突中的翻译后修饰的控制机制，并确定它们在受损轴突中的特定作用。具体地说，我们将确定如何随着时间的推移保持微管蛋白去乙酰化梯度，以维持轴突再生。我们还将确定微管蛋白酪氨酸化是否启动损伤信号的逆行运输，以激活促再生程序。我们的长期目标是对决定三叉神经节神经元再生反应的分子事件获得新的见解，并确定未来中枢神经系统损伤治疗干预的潜在靶点。

DESCRIPTION (provided by applicant): Lack of robust axonal regeneration represents one of the major barriers to recovery of neurological functions following injury to neurons within the central nervous system (CNS). In contrast, neurons in the peripheral nervous system (PNS) have a remarkable ability to regenerate after injury. The extent of axonal regeneration not only depends on the presence or absence of inhibitory cues in the environment, but also on the intrinsic growth capacity of damaged neurons. Indeed, blocking extracellular inhibitory influences alone is not sufficient to allow complete axon regeneration, emphasizing the need for a better understanding of the mechanisms controlling the intrinsic regenerative ability of injured neurons. The mechanisms that govern axon regeneration operate both in the cell body and locally in the axon. The local axonal responses allow injured neurons to signal back to the cell body and to transform their damaged axonal tips into a new growth- cone-like structure, two processes that are essential to initiate regeneration. In pursuing our studies on the response of axons to injury, we recently focused on the microtubule (MT) cytoskeleton. We found that the histone deacetylase HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration. HDAC5 accumulates and deacetylates tubulin at the tip of injured PNS, but not CNS axons. HDAC5-mediated tubulin deacetylation is essential for PNS neuron's ability to regenerate, but fails to occur in CNS neurons. In addition to tubulin deacetylation, we observed that PNS axon injury also increases tubulin tyrosination. Tubulin acetylation and tyrosination are known to contribute to the dynamics properties of MTs and to MT-dependent axonal transport. However, the signaling pathways elicited by injury, which regulate MT posttranslational modifications and the precise role these modifications play in axon regeneration remain elusive. Here we propose to uncover the mechanisms controlling MT post-translational modifications in injured axons and to establish their specific roles in injured axons. Specifically, we will determine how a tubulin deacetylation gradient is maintained over time to sustain axon regeneration. We will also determine whether tubulin tyrosination initiates the retrograde transport of injury signals to activate a pro- regenerative program. Our long-term goal is to gain new insights into the molecular events that dictate the regenerative response of PNS neurons, and identify potential targets for future therapeutic interventions in the setting of CNS injury.