How does Wlds protect severed axons?

描述(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，但对损伤或病变的轴突如何自我破坏知之甚少。最近关于小鼠沃勒变性慢分子(Wlds)的研究表明，轴突退化是轴突自我破坏的一个活跃过程。令人惊讶的是，在一些人类神经退行性疾病的小鼠模型中，Wlds还可以抑制化学侮辱后的轴突退化，并推迟疾病的发病。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。我们已经建立了第一个研究损伤诱导的轴突变性的果蝇模型，并表明小鼠Wlds也可以有效地抑制果蝇切断的轴突的轴突退化。这些数据表明，在果蝇和哺乳动物中，驱动轴突自毁的分子机制在果蝇和哺乳动物中保存得很好，并为研究轴突自毁的强大分子遗传学方法打开了大门。在这项建议中，我们将：(1)定义Wlds蛋白的结构域，以保护轴突；(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止轴突的自动破坏；以及(3)进行有史以来第一次正向遗传筛选，以阻止损伤后的轴突退化或Wlds的神经保护功能。这些研究代表了一项长期全面努力的开始，目的是了解轴突在受伤后如何自我破坏，以及WLDS如何冲击这些路径。我们预计，我们的发现将对我们对人类损伤后或疾病期间轴突变性的理解产生重大影响，我们识别的新分子将是治疗人类轴突病变的极佳候选分子。公共卫生相关性：脑损伤后或在神经系统疾病期间，神经纤维退化，大脑中的连接丢失，神经功能受到不可逆转的损害。我们正在研究一种特殊的分子WldS的细胞作用，这种分子可以抑制神经纤维的这种丢失。我们的工作将确定许多新的分子，这些分子将成为脑损伤后或神经疾病期间患者治疗的靶点。

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.