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，周围神经系统（PNS）中的神经元在受伤后具有显着的再生能力。轴突再生的程度不仅取决于环境中是否存在抑制信号，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不足以实现轴突完全再生，这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。控制轴突再生的机制在细胞体和局部轴突中都起作用。局部轴突反应允许受伤的神经元向细胞体发出信号，并将其受损的轴突尖端转化为新的生长锥状结构，这两个过程对于启动再生至关重要。 在研究轴突对损伤的反应时，我们最近关注微管（MT）细胞骨架。我们发现组蛋白脱乙酰酶 HDAC5 是一种新型损伤调节微管蛋白脱乙酰酶，控制轴突再生。 HDAC5 在受损的 PNS 尖端积聚并使微管蛋白去乙酰化，但不影响 CNS 轴突。 HDAC5 介导的微管蛋白脱乙酰化对于 PNS 神经元的再生能力至关重要，但在 CNS 神经元中却无法发生。除了微管蛋白脱乙酰化之外，我们还观察到 PNS 轴突损伤也会增加微管蛋白酪氨酸化。已知微管蛋白乙酰化和酪氨酸化有助于 MT 的动力学特性和 MT 依赖性轴突运输。然而，由损伤引起的调节 MT 翻译后修饰的信号通路以及这些修饰在轴突再生中发挥的确切作用仍然难以捉摸。在这里，我们建议揭示控制受损轴突中 MT 翻译后修饰的机制，并确定它们在受损轴突中的特定作用。具体来说，我们将确定如何随着时间的推移维持微管蛋白脱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传输以激活促再生程序。我们的长期目标是获得对决定 PNS 神经元再生反应的分子事件的新见解，并确定未来中枢神经系统损伤治疗干预的潜在目标。

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.