Non-apoptotic caspase activity in neurons

 描述（由申请人提供）：神经元中的非凋亡半胱天冬酶活性半胱天冬酶是一个保守的半胱氨酸蛋白酶家族，其协调凋亡和焦变性细胞死亡。半胱天冬酶活性在细胞死亡前不久被强烈诱导，并且半胱天冬酶缺陷的动物具有过量的细胞数量。因此，半胱天冬酶的激活通常被认为代表了细胞死亡的承诺点。然而，越来越多的证据表明，半胱天冬酶在健康细胞和组织中也具有非凋亡作用。据报道，哺乳动物和果蝇神经元使用半胱天冬酶修剪轴突和树突过程，这是功能性神经网络所必需的，除了空间限制之外，可能通过与凋亡类似的机制。然而，苍蝇和哺乳动物的半胱天冬酶已牵连在一系列其他细胞过程，包括细胞增殖和分化。在生长的轴突终末中检测到半胱天冬酶激活，并且没有细胞死亡的证据。然而，关键的未回答的问题仍然存在，包括什么类型的神经元显示caspase活性以及何时。此外，对健康神经元中半胱天冬酶活性的非凋亡功能知之甚少。已经开发了许多不同的半胱天冬酶生物传感器来检测神经元和其他细胞类型中的半胱天冬酶活化，然而可用的半胱天冬酶生物传感器不够敏感或持续来解决这些问题。因此，我们开发了一种新的双色caspase生物传感器，用于检测和研究果蝇神经元中的非凋亡caspase活性。我们建议确定哪些神经元表现出非凋亡的半胱天冬酶，并建立一个正常的神经元功能的半胱天冬酶的作用。这些研究需要获得新的见解，以了解连接caspase的正常与死亡功能的机制，因为这种平衡的失调可能会对神经退行性变做出重要贡献。

 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.