Roles of Cdk5 in neurodevelopment and neurodegeneration

我们试图回答两个问题：神经元在发育过程中是如何连接的，以及为什么它们在神经退行性疾病中会断开连接？ 在简单的无脊椎动物模型系统中开发神经退行性疾病模型具有很大的兴趣，这些模型系统为表征复杂过程的细胞事件并建立其分子遗传基础提供了无与伦比的实验能力。然而，使用果蝇来研究神经退行性变一直是有问题的，因为一般来说，它们要么依赖于高度人工的操作，例如在果蝇中高水平表达突变的人类基因，要么已经鉴定出明显影响果蝇神经元存活的基因，但与任何被证明在哺乳动物神经退行性变中起作用的基因或途径无关。我们现在已经确定了一种自然的，成年发病的果蝇神经退行性综合征的果蝇突变体的直系同源基因直接参与人类疾病，包括阿尔茨海默病和ALS。蛋白激酶Cdk5与其调节亚基p35一起是磷酸化细胞骨架蛋白以产生神经元缠结的主要激酶之一，所述神经元缠结是神经变性疾病的“tau蛋白病”类别的特征。此外，发现激活的Cdk5集中在阿尔茨海默病患者脑中的退化组织中，并且Cdk5的实验性激活诱导小鼠脑中的退化病变。我们已经产生了一个无效突变的基因编码的果蝇同源物的Cdk5激活亚基，p35，并发现它会导致成年发病的神经退行性变的果蝇大脑的特定部分，“蘑菇体”是学习和记忆的座位。 我们利用果蝇系统来询问由于Cdk5活性丧失而注定退化的神经元中最早的缺陷是什么，并发现了两种完全出乎意料的表型。首先，我们发现Cdk 5对于启动神经冲动的轴突部分的发育至关重要。这种细胞区室的不适当组织预计会导致神经细胞在神经回路中发挥作用的能力的严重缺陷。这种缺陷在Cdk5相关神经变性的启动或进展中发挥作用当然是合理的，但需要额外的实验来验证这一假设。其次，我们发现Cdk5控制着负责轴突和树突在特定发育阶段遗传程序分解的机制。在这里，这在病理性Cdk 5相关的神经元分解中的潜在意义也是清楚的，但需要更多的实验来充分理解这种联系。

We seek to answer two questions: how do neurons become connected during development, and why do they become disconnected during neurodegenerative disease? There is a great deal of interest in developing models of neurodegenerative diseases in simple, invertebrate model systems that provide unequaled experimental power for characterizing the cellular events of a complex process and establishing its molecular genetic basis. Use of Drosophila for studies of neurodegeneration have been problematic, however, since in general they have either relied on highly artificial manipulations, such as high-level expression of mutated human genes in the fly, or have identified genes that clearly affect neuronal survival in the fly but are not related to any gene or pathway demonstrated to play a role in neurodegeneration in mammals. We have now identified a natural, adult-onset neurodegenerative syndrome of Drosophila in flies mutant for the ortholog of a gene directly implicated in human diseases including Alzheimer Disease and ALS. The protein kinase Cdk5, together with its regulatory subunit, p35, is one of the major kinases that phosphorylates cytoskeletal proteins to generate the neurofibrillary tangles that are characteristic of the "tauopathy" class of neurodegenerative diseases. Moreover, activated Cdk5 is found concentrated in degenerating tissue in the brains of Alzheimer patients, and experimental activation of Cdk5 induces degenerating lesions in the mouse brain. We have generated a null mutation of the gene encoding the fly homolog of the Cdk5 activating subunit, p35, and find that it causes adult-onset neurodegeneration of a specific portion of the Drosophila brain, the "mushroom bodies" that are the seat of learning and memory. We took advantage of the Drosophila system to ask what are the earliest defects in neurons that are fated to degenerate from loss of Cdk5 activity, and found two completely unexpected phenotypes. First, we found that Cdk5 is essential for the development of the portion of an axon where nerve impulses are initiated. Improper organization of this cellular compartment is expected to cause profound defects in the ability of a nerve cell to act in a neural circuit. It is certainly plausible that such defects play a role in the initiation or progression of Cdk5-associated neurodegeneration, but additional experiments will be necessary to test this hypothesis. Second, we found that Cdk5 controls the machinery responsible for the genetically-programmed disassembly of axons and dendrites at particular developmental stages. Here as well, the potential significance for this in pathological Cdk5-associated disassembly of neurons is clear, but additional experiments will be necessary to fully understand the link.