Non-apoptotic caspase activity in neurons

 描述(由申请人提供)：神经元中的非凋亡性半胱氨酸酶活性Caspase是一个保守的半胱氨酸蛋白酶家族，可协调细胞的凋亡和嗜酸性细胞死亡。Caspase活性在细胞死亡前不久被强烈地诱导，而Caspase缺陷的动物有多余的细胞数量。因此，caspase的激活通常被认为是细胞死亡的承诺点。然而，越来越多的证据表明，在健康的细胞和组织中，半胱氨酸天冬氨酸酶也具有非凋亡作用。哺乳动物和果蝇的神经元已经被报道使用caspase来修剪轴突和树突，这是功能神经网络所必需的，除了空间受限之外，其潜在的机制与细胞凋亡相似。然而，苍蝇和哺乳动物的caspase还参与了一系列其他细胞过程，包括细胞的增殖和分化。在生长中的轴突终末检测到caspase激活，但没有细胞死亡的证据。然而，关键的悬而未决的问题仍然存在，包括哪些类型的神经元显示caspase活性，以及何时显示。此外，人们对健康神经元中caspase活性的非凋亡功能知之甚少。已经开发了许多不同的caspase生物传感器来检测神经元和其他类型细胞中的caspase激活，然而现有的caspase生物传感器不够灵敏或不够持久来解决这些问题。因此，我们为果蝇研制了一种新型的双色caspase生物传感器来检测和研究神经元中非凋亡性caspase的活性。我们建议确定哪些神经元表现出非凋亡性caspase，并确定caspase在正常神经元功能中的作用。这些研究需要对连接caspase正常和死亡功能的机制有新的见解，因为这种平衡的失调可能会导致神经退化。

 DESCRIPTION (provided by applicant): Non-apoptotic caspase activity in neurons Caspases are a family of conserved cysteine proteases that orchestrate apoptotic and pyroptotic cell death. Caspase activity is robustly induced shortly before cell death, and caspase-deficient animals have excess cell numbers. Therefore, activation of caspases is often assumed to represent a commitment point towards cell death. However, mounting evidence indicates that caspases also have non-apoptotic roles in healthy cells and tissues. Mammalian and Drosophila neurons have been reported to use caspases for pruning axonal and dendritic process, which is essential for functional neural networks, potentially by similar mechanisms as apoptosis except spatially restricted. However, fly and mammalian caspases have been implicated in a range of other cellular processes, including cell proliferation and differentiation. Caspase activation has been detected in growing axon terminals, and without evidence of cell death. However, the key unanswered questions remain, including what types of neurons display caspase activity and when. Furthermore, very little is known about the non- apoptotic functions of caspase activity in healthy neurons. A number of different caspase biosensors have been developed to detect caspase activation in neurons and other cell types, however available caspase biosensors are not sufficiently sensitive or sustained to address these questions. Therefore, we developed a new dual color caspase biosensor for Drosophila to detect and study non-apoptotic caspase activity in neurons. We propose to determine which neurons exhibit non-apoptotic caspase, and to establish a role for caspases in normal neuronal function. These studies are needed to gain new insights into the mechanisms that connect the normal versus death functions of caspases, as dysregulation of this balance could contribute importantly to neurodegeneration.