The effect of mitochondrial transport and function on synaptic integrity during ageing

衰老过程中线粒体运输和功能对突触完整性的影响

• 批准号: 2444948
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2444948
• 关键词: effect; mitochondrial; transport; function; synaptic

Mitochondria are small membrane-bound organelles that generate ATP(Kann & Kovacs, 2007). ATP is essential for neuronalfunction(Cai & Sheng, 2011), including the filling, release, and recycling of synaptic vesicles (Takeda & Ueda, 2017) and the maintenance of calcium homeostasis (Werth & Thayer, 1994). Efficient mitochondrial transport and proper mitochondrial distribution is critical to ensure mitochondria can service all parts of the neuron, especially highly energy-dependent regions such as the synapses (Cai & sheng, 2011). Furthermore, mitochondrial function and transport is important for the trafficking of other cargo, as intracellular transport is ATP-dependent (Zala et al., 2013).The Vagnoni lab found that mitochondrial transport decreases with ageing (Vagnoni et al., 2016), using a novel method to image cargo transport in live Drosophila by imaging the sensory neuron axons within the wing (Vagnoni & Bullock, 2016). Furthermore, the lab showed that experimentally elevating levels of mitochondrial transport in aged Drosophila neurons (by stimulating thecAMP/ PKA pathway) has a protective effect, reducing oxidative stress levels (Vagnoni & Bullock, 2018). The lab has preliminary evidence that amyloid precursors protein (APP), which is also transported by the kinesin motor, shows decreased trafficking during ageing. However, it is not clear whether this is linked to the defective mitochondrial transport effect. Synapses are junctions between a presynaptic neuron and a postsynaptic cell, usually another neuron (Sudhof, 2018). Synapses are essential for neurotransmission -the diffusion of neurotransmitters across the synapse and their subsequent detection by receptors on the postsynaptic cell surface (Sudhof, 2018). Cell adhesion molecules neurexin (on the presynaptic cell membrane) and neuroligin (on the postsynaptic cell membrane) tether the pre-and post-synaptic cells together, making them particularly important for synapse formation and maintenance (Craig & Kang, 2007). Studies have shown that neurexin and neuroligin are transported through neurons much like mitochondria, using the microtubule network and kinesin/ dynein motor proteins (Kneussel, 2011; Puthanveettil et al., 2008). Indeed, knockdown of kinesin-1 stops neurexin moving towards synapses, causing it to accumulate at the soma and axon initial segment (Neupert et al., 2015). Studies have shown that synaptic dysfunction occurs during ageing (Morrison & Baxter, 2012) and is a hallmark of several neurodegenerative diseases (Wishart et al., 2006). Neuroligin and neurexin have been shown to interact with amyloidogenic proteins, present in Alzheimer's disease, indicating an functional role for synapses in Alzheimer's pathogenesis (Brito-Moreira et al., 2017). In conclusion, it is clear mitochondria are important for synaptic health. The evidence shows that both mitochondrial transport dysfunction and synaptic dysfunction are associated with ageing. However, there are several unknowns. No study has unequivocally shown how defective mitochondrial transport affects synaptic stability, or the transport of other cargo like neurexin and neuroligin, during ageing. Furthermore, we do not know how defective mitochondrial transport affects the trafficking of neurodegenerative disease-relevant proteins like APP during ageing. These questions are important as they would enable us to better understand the factors causing age-related decline in synapse function, a common feature of brain dysfunction.

线粒体是产生ATP的小的膜结合细胞器（Kann & Kovacs，2007）。ATP对神经元功能至关重要（Cai & Sheng，2011），包括突触囊泡的填充、释放和再循环（Takeda &上田，2017）以及钙稳态的维持（Werth & Thayer，1994）。有效的线粒体运输和适当的线粒体分布对于确保线粒体能够服务于神经元的所有部分至关重要，特别是高度能量依赖的区域，如突触（Cai & sheng，2011）。此外，线粒体功能和转运对于其他货物的运输是重要的，因为细胞内转运是ATP依赖性的（扎拉et al.，2013). Vagnoni实验室发现，线粒体转运随着衰老而减少（Vagnoni等人，2016），使用一种新方法通过对翅膀内的感觉神经元轴突进行成像来对活果蝇中的货物运输进行成像（Vagnoni &布洛克，2016）。此外，该实验室表明，实验性地提高老年果蝇神经元的线粒体转运水平（通过刺激thecAMP/ PKA途径）具有保护作用，降低氧化应激水平（Vagnoni &布洛克，2018）。该实验室有初步证据表明，淀粉样前体蛋白（APP），这也是由驱动蛋白马达运输，显示在衰老过程中减少贩运。然而，目前尚不清楚这是否与线粒体转运效应缺陷有关。突触是突触前神经元和突触后细胞之间的连接，通常是另一个神经元（Sudhof，2018）。突触对于神经传递至关重要--神经递质穿过突触的扩散以及随后被突触后细胞表面的受体检测（Sudhof，2018）。细胞粘附分子neurexin（在突触前细胞膜上）和neuroligin（在突触后细胞膜上）将突触前和突触后细胞拴在一起，使得它们对于突触形成和维持特别重要（克雷格和康，2007）。研究已经表明，neurexin和neuroligin使用微管网络和驱动蛋白/动力蛋白马达蛋白通过神经元转运，非常像线粒体（Kneussel，2011; Puthanveettil et al.，2008年）。事实上，驱动蛋白-1的敲低阻止神经节蛋白向突触移动，导致其在索马和轴突起始段处积累（Neupert et al.，2015年）。研究表明，突触功能障碍发生在衰老过程中（莫里森和巴克斯特，2012），并且是几种神经退行性疾病的标志（Wishart等人，2006年）。已经显示神经连接素和neurexin与阿尔茨海默病中存在的淀粉样蛋白相互作用，表明突触在阿尔茨海默病发病机制中的功能作用（Brito-Moreira et al.，2017年）。总之，线粒体对突触健康很重要。有证据表明，线粒体转运功能障碍和突触功能障碍都与衰老有关。然而，有几个未知数。没有研究明确表明线粒体转运缺陷如何影响突触稳定性，或其他货物的运输，如neurexin和neuroligin，在衰老过程中。此外，我们不知道线粒体转运缺陷如何影响衰老过程中神经退行性疾病相关蛋白（如APP）的运输。这些问题很重要，因为它们将使我们能够更好地了解导致与年龄相关的突触功能下降的因素，这是大脑功能障碍的一个共同特征。