Septin 3 regulates synaptic vesicle endocytosis

神经细胞具有独特的特性，比如它们能够产生离细胞体很远的轴突（分化），它们能够与其他细胞接触，并通过神经末梢内突触囊泡释放神经递质（胞吐）和突触囊泡的再循环（内吞作用）来启动交流。这些事件主要由大量突触特异性蛋白控制，并受信号分子cGMP的部分调控，cGMP主要刺激PKG酶。在NHMRC支持的前期研究中，我们发现了许多被PKG磷酸化和激活的蛋白，其中septin 3是本研究的重点。我们最初克隆了septin 3作为一个由10个基因组成的家族的新成员，这些基因对细胞分裂至关重要。一些隔素聚集成细丝，使两个新的子细胞最终分离。当纤维的形成受到干扰时，某些蛋白酶最终会形成微小的团块，这些团块在阿尔茨海默氏症患者死后的大脑中被发现，这表明它们可能会导致这种疾病。然而，septin 3与大多数septin不同，因为它是一种脑特异性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。唯一已知的另一种脑特异性septin是CDCrel-1，它调节胞吐作用的蛋白质机制。我们将检验G-septin也是突触囊泡内吞的调节因子的假设。我们将确定septin是否代表cGMP信号传导控制内吞作用的交汇点。更好地了解septin 3和内吞作用对于理解大脑疾病并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.