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，但对于受损或患病轴突如何自我破坏知之甚少。最近对小鼠沃勒氏变性慢分子（Wlds）的研究表明，轴突变性是一个主动的轴突自毁过程，它能有效地保护被切断的轴突不发生变性。令人惊讶的是，在许多人类神经退行性疾病的小鼠模型中，Wlds还可以抑制化学损伤后的轴突变性，并延缓疾病的发作。因此，wds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wds也可以有效地抑制切断的果蝇轴突的轴突变性。这些数据表明，在果蝇和哺乳动物中，损伤后驱动轴突自毁的分子机制是保守的，并打开了仅在果蝇中可用的强大的分子遗传学方法来研究轴突自毁的大门。在这个提议中，我们将：(1)定义wds蛋白保护轴突所必需的结构域；(2)确定wld是否与泛素蛋白酶体、NAD生物合成或凋亡机制相互作用，以阻止轴突的自毁；(3)对损伤后阻断轴突退化或wds神经保护功能的突变进行首次遗传筛选。这些研究代表了长期全面努力的开始，以了解轴突在损伤后如何自我破坏，以及wds如何影响这些途径。我们期望我们的发现对我们对人类损伤后或疾病期间轴突退化的理解产生重大影响，我们鉴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，脑内连接丧失，神经功能不可逆转地受损。我们正在研究一种特殊分子wld的细胞作用，它能抑制神经元纤维的流失。我们的工作将确定许多新的分子，这些分子将成为治疗脑损伤或神经系统疾病患者的靶点。

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.