Spatial Considerations in Neuronal Survival Signals

描述（由申请人提供）：靶源性神经营养因子（NTs）对于遇到这些配体的轴突的存活和远端细胞体的存活都是必需的。在了解NT信号如何促进细胞体存活方面取得了很大进展。然而，轴突的存活或退化是由与调节细胞体存活和死亡的分子成分重叠但不相同的分子成分控制的。因此，一个重要的未解决的问题是目标衍生的NTs如何参与调节成分来促进轴突存活并防止轴突在发育和整个生命过程中的退化。在初步研究中，我和我的同事发现bclw（或bcl2l2）是bcl2家族成员，对nt依赖性轴突生存至关重要。Bclw是富含轴突的bcl2家族成员，在小鼠模型中，Bclw可以防止轴突进行性变性，并且Bclw对淀粉样蛋白毒性具有神经保护作用。我们证明bclw是一种逆行反应基因（RRG），它可以通过NT对远端轴突的刺激选择性上调。令人惊讶的是，bclw mRNA存在于轴突和细胞体中，NT刺激远端轴突增加了两个位置的bclw mRNA水平。为了了解NTs如何调节轴突活力和防止退化，我们将确定远端轴突的NT刺激如何协调调节bclw mRNA的转录、转运和翻译，以调节轴突bclw的水平，从而保护连接功能回路的长轴突。我们有三个目的来测试我们的神经网络调节轴突存活途径的模型，并探讨以轴突变性为特征的神经系统疾病的影响。目的1。为了验证NT刺激轴突促进新合成bclw mrna转录和轴突转运的假设。目标2。为了验证RNA结合蛋白SFPQ对bclw调控至关重要的假设。目标3。验证bclw在轴突中局部翻译以促进长轴突存活的假说。综上所述，这些研究将为NT信号如何在发育和成熟的神经系统的空间限制中发挥作用提供新的理解。最近的研究集中在轴突变性对退行性疾病的重要性，包括周围神经病、ALS和阿尔茨海默病；我们的研究将确定支持轴突健康的途径，并可能在这种疾病中受到影响。此外，参与这些nt依赖通路并在功能回路中保存连接神经元的干预措施在多种神经系统疾病中具有巨大的治疗潜力。

DESCRIPTION (provided by applicant): Target derived neurotrophins (NTs) are required both for survival of the axon that encounters these ligands and for survival of the remote cell body. Much progress has been made in understanding how NT signals promote cell body survival. However, survival or degeneration of axons is controlled by molecular components that overlap with, but are not identical to, those that regulate cell body survival and death. Therefore an important unresolved question is how target derived NTs engage regulatory components to foster axonal survival and prevent axonal degeneration during development and throughout life. In preliminary studies, my colleagues and I identified bclw (or bcl2l2) as the bcl2 family member critical for NT-dependent axonal viability. Bclw is the bcl2 family member that is enriched in axons, bclw prevents progressive axonal degeneration in mouse models, and bclw is neuroprotective against ¿-amyloid toxicity. We demonstrated that bclw is a retrograde response gene (RRG), which is selectively upregulated by NT stimulation of distal axons. Surprisingly, mRNA for bclw is present in axons as well as in cell bodies, and NT stimulation of distal axons increases the levels of bclw mRNAs in both locations. To understand how NTs regulate axonal viability and prevent degeneration we will determine how NT stimulation of distal axons coordinately regulates transcription, transport and translation of bclw mRNA to adjust the level of axonal bclw, and thereby preserve the long axons connecting a functioning circuit. We have three aims to test our model for NT regulation of axonal survival pathways, and to probe the implications for neurologic disorders characterized by axonal degeneration. Aim 1. To test the hypothesis that NT stimulation of axons promotes transcription and axonal transport of newly synthesized bclw mRNAs. Aim 2. To test the hypothesis that the RNA binding protein SFPQ is critical for bclw regulation. Aim 3. To test the hypothesis that bclw is locally translated in axons to promote viability of long axons. Together these studies will provide a new understanding of how NT signaling functions within the spatial constraints of the developing and mature nervous system. Recent studies have focused attention on the importance of axonal degeneration for degenerative disorders, including peripheral neuropathies, ALS and Alzheimer's disease; our studies will identify pathways that support axonal health and are likely to be affected in such disorders. Furthermore, interventions that engage these NT-dependent pathways and preserve connected neurons within a functional circuit have great therapeutic potential in diverse neurologic diseases.