How does Wlds protect severed axons?

描述（由申请人提供）：轴突变性发生在神经系统损伤后和神经退行性疾病期间，但对受损或患病的轴突如何破坏自身知之甚少。最近对小鼠Wallerian变性慢分子（Wlds）的研究表明，轴突变性是轴突自身破坏的一个主动过程，Wlds可以有效地保护切断的轴突免于变性。令人惊讶的是，Wlds还可以抑制化学损伤后的轴突变性，并在许多人类神经退行性疾病的小鼠模型中延迟疾病发作。因此，Wlds是一种广泛的神经保护分子，了解其分子作用至关重要。我们已经开发了第一个果蝇模型来研究损伤诱导的轴突变性，并表明小鼠Wlds也可以有效地抑制切断的果蝇轴突中的轴突变性。这些数据表明，损伤后驱动轴突自动破坏的分子机制在果蝇和哺乳动物中是保守的，并为研究轴突自动破坏的强大分子遗传学方法打开了大门。在本提案中，我们将：（1）确定Wlds蛋白保护轴突所必需的结构域;（2）确定Wlds是否与泛素蛋白酶体、NAD生物合成或凋亡机制相互作用以阻断轴突自动破坏;和（3）对阻断损伤后轴突变性或Wlds神经保护功能的突变进行首次正向遗传筛选。这些研究代表了长期全面努力的开始，以了解轴突如何在损伤后破坏自己，以及Wlds如何影响这些通路。我们希望我们的研究结果对我们理解人类损伤后或疾病期间的轴突变性产生重大影响，我们确定的新分子将成为人类轴突病治疗干预的优秀候选者。公共卫生相关性：脑损伤后或神经系统疾病期间，神经纤维退化，脑中的连接丢失，神经功能不可逆地受损。我们正在研究一种特殊分子WldS的细胞作用，它可以抑制神经纤维的损失。我们的工作将确定许多新的分子，这些分子将成为脑损伤或神经系统疾病患者治疗的目标。

DESCRIPTION (provided by applicant): Axon degeneration occurs after nervous system injury and during neurodegenerative diseases but very little is known about how injured or diseased axons destroy themselves. Recent work on the mouse Wallerian degeneration slow molecule (Wlds), which potently protects severed axons from degeneration, has revealed that axon degeneration is an active process of axon auto-destruction. Amazingly, Wlds can also suppress axon degeneration after chemical insult and delay disease onset in a number of mouse models of human neurodegenerative disease. Wlds is therefore a broadly neuroprotective molecule and understanding its molecular action is of paramount importance. We have developed the first Drosophila model to study injury-induced axon degeneration and shown that mouse Wlds can also potently suppress axon degeneration in severed Drosophila axons. These data indicate that the molecular mechanism that drive axon auto-destruction after injury are well-conserved in Drosophila and mammals, and open the door to powerful molecular-genetic approaches only available in Drosophila to study axon auto-destruction. In this proposal we will: (1) define the domains of the Wlds protein essential for it to protect axons; (2) determine whether Wlds interacts with the ubiquitin proteasome, NAD biosynthetic, or apoptotic machinery to block axon auto-destruction; and (3) perform the first ever forward genetic screens for mutation that block axon degeneration after injury or Wlds neuroprotective function. These studies represent the beginning of a long-term comprehensive effort to understand how axons destroy themselves after injury, and how Wlds impinges upon these pathways. We expect our findings to have a major impact on our understanding of axon degeneration after injury or during disease in humans, and the novel molecules we identify will be excellent candidates for therapeutic intervention in human axonopathies. PUBLIC HEALTH RELEVANCE: After brain injury or during neurological disease neuronal fibers degenerate, connections in the brain are lost, and neural function is irreversibly compromised. We are studying the cellular action of an extraordinary molecule, WldS, which suppresses this loss of neuronal fibers. Our work will identify many new molecules that will be targets for treatment of patients after brain injury or during neurological disease.