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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Loss of α-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function
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Loss of α-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function

机译：ROSA22小鼠中α-微管蛋白多谷氨酰化的丧失与KIF1A的靶向异常和​​突触功能调节有关

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摘要

Microtubules function as molecular tracks along which motor proteins transport a variety of cargo to discrete destinations within the cell. The carboxyl termini of α- and β-tubulin can undergo different posttranslational modifications, including polyglutamylation, which is particularly abundant within the mammalian nervous system. Thus, this modification could serve as a molecular "traffic sign" for motor proteins in neuronal cells. To investigate whether polyglutamylated α-tubulin could perform this function, we analyzed ROSA22 mice that lack functional PGs1, a subunit of α-tubulin-selective polyglutamylase. In wild-type mice, polyglutamylated α-tubulin is abundant in both axonal and dendritic neurites. ROSA22 mutants display a striking loss of polyglutamylated α-tubulin within neurons, including their neurites, which is associated with decreased binding affinity of certain structural microtubule-associated proteins and motor proteins, including kinesins, to microtubules purified from ROSA22-mutant brain. Of the kinesins examined, KIF1A, a subfamily of kinesin-3, was less abundant in neurites from ROSA22 mutants in vitro and in vivo, whereas the distribution of KIF3A (kinesin-2) and KIF5 (kinesin-1) appeared unaltered. The density of synaptic vesicles, a cargo of KIF1A, was decreased in synaptic terminals in the CA1 region of hippocampus in ROSA22 mutants. Consistent with this finding, ROSA22 mutants displayed more rapid depletion of synaptic vesicles than wild-type littermates after high-frequency stimulation. These data provide evidence for a role of polyglutamylation of α-tubulin in vivo, as a molecular traffic sign for targeting of KIF1 kinesin required for continuous synaptic transmission.
机译：微管起分子轨道的作用，运动蛋白沿着该分子轨道将各种货物运输到细胞内的离散目的地。 α-和β-微管蛋白的羧基末端可以经历不同的翻译后修饰，包括聚谷氨酰化，这在哺乳动物的神经系统中特别丰富。因此，这种修饰可以作为神经元细胞中运动蛋白的分子“交通标志”。为了研究聚谷氨酰胺化的α-微管蛋白是否可以执行此功能，我们分析了缺少功能性PGs1（α-微管蛋白选择性聚谷氨酰胺酶的亚基）的ROSA22小鼠。在野生型小鼠中，轴突和树突状神经突中都富含谷氨酰胺化的α-微管蛋白。 ROSA22突变体在神经元（包括其神经突）中显示出明显的谷氨酰胺化α-微管蛋白损失，这与某些结构微管相关蛋白和运动蛋白（包括驱动蛋白）与从ROSA22突变脑中纯化的微管的结合亲和力降低有关。在所研究的驱动蛋白中，在体外和体内，来自ROSA22突变体的神经突中KIF1A属于驱动蛋白3的一个亚家族，而KIF3A（驱动蛋白-2）和KIF5（驱动蛋白-1）的分布似乎没有改变。在ROSA22突变体中，海马CA1区突触末端的KIF1A突触小泡的密度降低。与该发现一致的是，高频刺激后，ROSA22突变体比野生型同窝仔动物显示出更快的突触囊泡损耗。这些数据提供了在体内α-微管蛋白的聚谷氨酰化作用的证据，作为连续突触传递所需的靶向KIF1驱动蛋白的分子交通标志。

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