Septin 3 regulates synaptic vesicle endocytosis

神经细胞具有独特的特性，比如它们能够发出距离细胞体很远的轴突(分化)，它们能够与其他细胞接触，并通过从神经末梢内的突触小泡释放神经递质来启动通信(胞吐作用)，以及这些突触小泡的循环(内吞作用)。这些事件主要由大量突触特异性蛋白控制，部分受信号分子cGMP调控，cGMP主要刺激PKG酶。在之前由NHMRC支持的研究中，我们发现了许多被PKG磷酸化并激活的蛋白质。其中一种是Septin 3，是这项提案的重点。我们最初克隆了Septin 3，作为细胞分裂所必需的10个基因家族中的一个新成员。一些隔质以细丝的形式聚集在一起，使两个新的子细胞最终分离。当细丝形成受到干扰时，在阿尔茨海默病患者死后大脑中发现的某些隔质最终会在显微镜下形成团块，这表明它们可能与疾病有关。然而，Septin 3与大多数Septin不同，因为它是一种大脑特有的Septin，我们在神经元中发现了它，并发现它高度集中在神经末梢，而神经末梢通常与细胞分裂无关。唯一已知的另一种大脑特异性Septin，CDCrel-1，调节胞吐的蛋白质机制。我们将检验G-Septin也是突触小泡内吞的调节因子的假设。我们将确定Septin是否代表cGMP信号的汇聚点来控制内吞作用。更好地了解Septin 3和内吞作用对于了解大脑疾病和最终开发更好的治疗方法至关重要。

Nerve cells have unique properties like their ability to put out axons that reach long distances from the cell body (differentiation), their ability to make contacts with other cells and initiate communication by the release of neurotransmitters from synaptic vesicles inside nerve endings (exocytosis) and the recycling of those synaptic vesicles (endocytosis). These events are mainly controlled by a large number of synapse-specific proteins, and partly regulated by a signalling molecule, cGMP, which mainly stimulates the enzyme PKG. In previous studies supported by the NHMRC we identified many proteins that are phosphorylated and activated by PKG. One of them, septin 3, is the focus of this proposal. We initially cloned septin 3 as a new member of a family of 10 genes that are essential for cell division. Some septins assemble as filaments that allow the two new daughter cells to finally separate. When the filament formation is perturbed certain septins end up in microscopic clumps that are found in the post-mortem brains of people affected by Alzheimer's disease, suggesting they might contribute to the disease. However, septin 3 is unlike most septins because it is a brain-specific septin, which we found in neurons and found to be highly concentrated in nerve terminals, locations not normally associated with cell division. The only other known brain-specific septin, CDCrel-1, regulates the protein machinery of exocytosis. We will examine the hypothesis that G-septin is also a regulator of synaptic vesicle endocytosis. We will determine whether septin represents a convergence point for cGMP signalling to control endocytosis. A better understanding of septin 3 and endocytosis is crucial to understanding brain disorders and ultimately developing better therapies.