Golgi-independent secretory trafficking through recycling endosomes in neuronal dendrites and spines.
Golgi-independent secretory trafficking through recycling endosomes in neuronal dendrites and spines.
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DOI：
10.7554/elife.27362
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发表时间：
2017-09-06
期刊：
影响因子：
7.7
通讯作者：
Kennedy MJ
中科院分区：
文献类型：
--
作者：
Bowen AB;Bourke AM;Hiester BG;Hanus C;Kennedy MJ
神经元面临的挑战是调节其巨大的，复杂的树突状结构内的膜蛋白的丰度，分布和剧目。虽然内质网（ER）支持树突翻译，但大多数树突缺乏高尔基体（GA），这是传统分泌运输的重要细胞器。因此，分泌货物是否通过非经典途径在树突中局部运输仍然是一个基本问题。在这里，我们定义了大鼠皮层神经元中关键突触分子的树突运输路线。ER退出后，AMPA型谷氨酸受体GluA1和神经连接素1在空间上受限地进入树突分泌途径，并在到达质膜之前积累在位于树突和棘中的再循环内体（RE）中。令人惊讶的是，即使GA功能被破坏，GluA1表面传递也会发生。因此，除了它们在蛋白质回收中的典型作用之外，RE还通过专门的GA独立的贩运网络介导神经元树突和棘中的正向分泌贩运。所有的细胞都必须在正确的时间和适当的数量产生、分类和运送分子构建模块到正确的地方。这对神经元尤其重要，神经元是体内最大、结构最复杂的细胞。一个典型的神经元包括一个细胞体，细胞体上覆盖着称为树突的分支，加上一个称为轴突的单一索状结构。树突接收来自其他神经元的输入，并以电信号的形式将信息传递给细胞体。细胞体处理这些电信号，然后产生的信号沿着轴突传播到远端的终端。轴突终末又通过称为突触的连接将信号传递给其他神经元的树突。为了使突触正常工作，树突周围的膜需要包含能够检测传入信号的受体蛋白。这些蛋白质必须不断补充，这就提出了一个问题：新产生的受体分子如何穿梭到树突内的适当位置。一系列被称为高尔基复合体的区室在许多不同类型的细胞中处理新产生的蛋白质方面起着重要作用。当蛋白质通过高尔基体时，通道壁内的酶通过添加或去除分子基团来修饰蛋白质。因此，有人提出，突触受体蛋白通过神经元到达树突的路线总是包括访问高尔基体。然而，神经元中的高尔基复合体主要局限于细胞体，这就提出了一个问题，即树突内局部产生的蛋白质是否可以在不访问高尔基复合体的情况下到达附近的突触。Bowen等人用显微镜观察培养皿中神经元中突触受体蛋白的运动。实验表明，蛋白质在离开细胞体后，会在树突上停留一段时间。然而，一些突触蛋白到达树突时根本不通过高尔基体，这表明神经元比其他类型的细胞更不依赖高尔基体来处理新产生的蛋白质。基因突变阻止蛋白质找到它们所需的目的地，或者破坏高尔基体等运输站内酶的工作，导致许多人类疾病。了解蛋白质如何到达健康细胞内的特定目的地也有助于揭示当这一过程失败时会发生什么。
Neurons face the challenge of regulating the abundance, distribution and repertoire of integral membrane proteins within their immense, architecturally complex dendritic arbors. While the endoplasmic reticulum (ER) supports dendritic translation, most dendrites lack the Golgi apparatus (GA), an essential organelle for conventional secretory trafficking. Thus, whether secretory cargo is locally trafficked in dendrites through a non-canonical pathway remains a fundamental question. Here we define the dendritic trafficking itinerary for key synaptic molecules in rat cortical neurons. Following ER exit, the AMPA-type glutamate receptor GluA1 and neuroligin 1 undergo spatially restricted entry into the dendritic secretory pathway and accumulate in recycling endosomes (REs) located in dendrites and spines before reaching the plasma membrane. Surprisingly, GluA1 surface delivery occurred even when GA function was disrupted. Thus, in addition to their canonical role in protein recycling, REs also mediate forward secretory trafficking in neuronal dendrites and spines through a specialized GA-independent trafficking network. All cells must produce, sort and deliver molecular building blocks to the right places at the right time and in appropriate amounts. This is particularly important for neurons, which are the largest and most structurally complex cells in the body. A typical neuron consists of a cell body covered in branches called dendrites, plus a single cable-like structure known as an axon. Dendrites receive inputs from other neurons and relay the information to the cell body in the form of electrical signals. The cell body processes these electrical signals and the resulting signals then travel along the axon to terminals at the far-end. The axon terminals in turn pass the signals on to the dendrites of other neurons via junctions called synapses. For synapses to work correctly, the membranes surrounding the dendrites need to contain receptor proteins that can detect incoming signals. These proteins must be continually replenished, raising the question of how newly made receptor molecules are shuttled to the appropriate locations within the dendrites. A series of compartments called the Golgi complex play an important role in processing newly-made proteins in many different types of cells. As proteins pass through the Golgi, enzymes within the tunnel walls modify the proteins by adding or removing molecular groups. Therefore, it has been suggested that the route that the synapse receptor proteins take through the neuron to reach the dendrites always includes a visit to the Golgi. However, the Golgi complex in neurons is mostly confined to the cell body, raising the question of whether proteins that are locally produced within dendrites can make the journey to nearby synapses without visiting the Golgi complex. Bowen et al. used a microscope to follow the movements of synapse receptor proteins through neurons grown in a dish. The experiments show that proteins destined for the dendrites make a number of stops after leaving the cell body. However, some synaptic proteins reach the dendrites without passing through the Golgi at all, suggesting neurons are much less dependent on the Golgi to process newly-made proteins than other types of cells. Genetic mutations that prevent proteins from finding their way to their required destinations, or that disrupt the work of enzymes inside trafficking stations like the Golgi, cause numerous human diseases. Understanding how proteins travel to specific destinations inside healthy cells should also help reveal what happens when this process fails.