MICROTUBULE POST-TRANSLATIONAL MODIFICATIONS IN AXON REGENERATION

轴突再生中的微管翻译后修饰

• 批准号: 8651957
• 负责人: Valeria Cavalli
• 金额: $ 32.92万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651957
• 关键词: Acetylation; Axon; Axonal Transport; Back; Biological Assay; Calcium; Cell Nucleus; Confocal Microscopy; Cues; Cytoskeleton; Data; Deacetylase; Deacetylation; Electron Microscopy; Environment; Enzymes; Event; Future; Goals; Growth; Growth Cones; HDAC5 gene; Histone Deacetylase; Injury; JNK-activating protein kinase; Laboratories; Lesion; MAPK8 gene; Maintenance; Measures; Mediating; Microtubules; Modification; Molecular; Morphology; Natural regeneration; Nervous System Physiology; Neuraxis; Neurobiology; Neurons; Nuclear Export; Pathway interactions; Peripheral; Peripheral Nervous System; Play; Post-Translational Protein Processing; Problem Solving; Process; Property; Recovery; Role; Signal Pathway; Signal Transduction; Site; Structure; Testing; Therapeutic Intervention; Time; Tubulin; Vesicle; axon regeneration; central nervous system injury; extracellular; injured; insight; knock-down; mouse model; mutant; nerve injury; neuronal cell body; new growth; novel; programs; public health relevance; regenerative; research study; response; retrograde transport; small hairpin RNA; tyrosyltubulin ligase

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.

描述（由申请方提供）：缺乏稳健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。相反，周围神经系统（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信号的存在与否，还取决于受损神经元的内在生长能力。事实上，单独阻断细胞外抑制作用不足以使轴突完全再生，强调需要更好地理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在细胞体和轴突局部都起作用。局部轴突反应允许受损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样结构，这两个过程对于启动再生至关重要。 在进行我们的研究轴突损伤的反应，我们最近集中在微管（MT）的细胞骨架。我们发现组蛋白去乙酰化酶HDAC5是一种新的损伤调节微管蛋白去乙酰化酶，控制轴突再生。HDAC 5在受损的PNS的尖端积累和脱乙酰化微管蛋白，但不是CNS轴突。HDAC5介导的微管蛋白去乙酰化对于PNS神经元的再生能力是必需的，但在CNS神经元中不发生。除了微管蛋白脱乙酰化，我们观察到PNS轴突损伤也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的动力学性质和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是难以捉摸的。在这里，我们建议揭示机制控制MT翻译后修饰损伤轴突，并建立其在损伤轴突的具体作用。具体来说，我们将确定如何维持微管蛋白脱乙酰梯度随着时间的推移，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。我们的长期目标是获得新的见解的分子事件，决定PNS神经元的再生反应，并确定潜在的目标，为未来的治疗干预设置中枢神经系统损伤。