Disruption of the MAP1B-related protein FUTSCH leads to changes in the neuronal cytoskeleton, axonal transport defects, and progressive neurodegeneration in Drosophila
Disruption of the MAP1B-related protein FUTSCH leads to changes in the neuronal cytoskeleton, axonal transport defects, and progressive neurodegeneration in Drosophila
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DOI：
10.1091/mbc.e04-11-1004
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发表时间：
2005-05-01
影响因子：
3.3
通讯作者：
Kretzschmar, D
中科院分区：
文献类型：
--
作者：
da Cruz, AB;Schwärzel, M;Kretzschmar, D
神经元轴突和树突的形成依赖于功能性细胞骨架。细胞骨架成分已被证明在成年期神经系统的维持中发挥重要作用，神经丝和微管相关蛋白（MAP）的变化与各种神经退行性疾病有关。在这里，我们表明，Futsch，果蝇同源物的MAP1B，参与进行性神经退行性变。虽然Futsch在整个CNS中广泛表达，但futsch（olk）的变性主要发生在嗅觉系统和蘑菇体中。与Futsch的预测功能一致，我们发现微管网络异常和轴突运输缺陷。成人大脑的退化之前是学习缺陷，揭示了可检测水平的细胞死亡之前的神经元功能障碍。Futsch受果蝇脆性X智力低下基因的负调控，该基因的突变延迟了Futsch（olk）神经变性的发生。通过表达蝇或牛tau获得类似的效果，表明一定程度的MAP功能冗余。futsch（olk）突变体表现出人类神经退行性疾病的几个特征，提供了一个机会，研究MAP在进行性神经退行性疾病中的作用，在实验上可访问的，在体内模型系统。
The elaboration of neuronal axons and dendrites is dependent on a functional cytoskeleton. Cytoskeletal components have been shown to play a major role in the maintenance of the nervous system through adulthood, and changes in neurofilaments and microtubule-associated proteins (MAPs) have been linked to a variety of neurodegenerative diseases. Here we show that Futsch, the fly homolog of MAP1B, is involved in progressive neurodegeneration. Although Futsch is widely expressed throughout the CNS, degeneration in futsch(olk) primarily occurs in the olfactory system and mushroom bodies. Consistent with the predicted function of Futsch, we find abnormalities in the microtubule network and defects in axonal transport. Degeneration in the adult brain is preceded by learning deficits, revealing a neuronal dysfunction before detectable levels of cell death. Futsch is negatively regulated by the Drosophila Fragile X mental retardation gene, and a mutation in this gene delays the onset of neurodegeneration in futsch(olk). A similar effect is obtained by expression of either fly or bovine tau, suggesting a certain degree of functional redundancy of MAPs. The futsch(olk) mutants exhibit several characteristics of human neurodegenerative diseases, providing an opportunity to study the role of MAPs in progressive neurodegeneration within an experimentally accessible, in vivo model system.