Investigating the connection between cytoskeletal and mitochondrial homeostasis during ageing

项目摘要（最多4000个字符，包括空格/回车）-来自原提案衰老伴随着运动、感觉和认知功能的下降，都严重影响人类的健康。因此，迫切需要更好地了解衰老过程中神经元衰退背后的精确生理过程。据报道，老年大脑神经元的各种亚细胞变化包括微管细胞骨架的改变、线粒体定位或功能的改变、自身吞噬体-溶酶体系统的效率低下、轴突萎缩和突触退化，最终导致神经元通信缺陷。我们假设这些变化并不是分开的，它们之间存在因果联系，并遵循逐步恶化的级联。线粒体是突触的重要组成部分，提供能量、代谢物和钙缓冲，对突触的功能至关重要。因此，有必要维持一个健康的突触线粒体池，并确保通过线粒体自噬清除受损的线粒体。有丝分裂依赖于自噬体-溶酶体系统。微管协调这些细胞器的组织和功能，并去除有缺陷的线粒体。这项工作的总体目标是研究微管衰变是否会导致细胞器功能障碍，并确定这种病理途径是否可以解释轴突老化。我们的详细目标是：1 .建立神经元衰老过程中线粒体功能的变化。研究微管网络的诱导变化是否与衰老神经元的线粒体病理相似3 .建立年龄相关微管扰动与线粒体功能障碍（如自噬/自噬损伤）之间的潜在机制确定这种改变是否有助于老化大脑中神经元的萎缩，并研究微管是否为改善线粒体健康提供了新的靶点。我们将使用我们已经建立的果蝇在体内和原代神经元培养中的大脑神经元衰老模型，以及哺乳动物细胞模型，包括来自年轻人和老年人的人类细胞。我们将利用先进的成像技术、细胞和分子生物学、生物化学和遗传学来研究线粒体生物学、自噬体和微管细胞骨架在衰老背景下的联系。我们的目标是为衰老过程中神经元退化提供新的解释和潜在的治疗策略。

Project summary (maximum of 4000 characters including spaces/returns) -from original proposal Ageing is accompanied by the decline in motor, sensory and cognitive functions, all severely impacting on human health. It is of high urgency to gain a better understanding of the precise physiological processes underlying neuronal decay during ageing.Various subcellular changes reported for neurons of aged brains include alterations in their microtubule cytoskeleton, changes in mitochondrial localisation or function, inefficient auto-phagosome-lysosome systems, axonal atrophy and deterioration of synapses culminating in neuronal communication deficits. We hypothesise that these changes are not separate and there are causative links between them that follow a stepwise cascade of deterioration. Mitochondria are vital components of synapses, critical for their function by providing energy, metabolites and calcium buffers. It is therefore necessary to maintain a healthy pool of synaptic mitochondria and to ensure the clearance of damaged ones by mitophagy. Mitophagy depends on the autophagosome-lysosome system. Microtubules coordinate the organisation and function of these organelles and the removal of faulty mitochondria. The overarching aim of this work is to study whether microtubule decay can lead to organelle dysfunction and to establish whether this pathological path can explain axonal ageing. Our detailed objectives are:1 To establish the changes in mitochondrial function during neuronal ageing. 2 To investigate whether induced changes in microtubule networks mimic mitochondrial pathologies known from ageing neurons.3 To establish underlying mechanisms linking age-related microtubule perturbation and mitochondrial dysfunction such as the impairment of autophagy/mitophagy.4 To establish whether such alteration contributes to the atrophy of neurons in the ageing brain and study whether microtubules provide a novel target to improve the health of mitochondria. We will use our well-established Drosophila models of neuronal ageing in the brain in vivo and in primary neuronal cultures, as well as mammalian cell models including human cells from young and old individuals. We will study the connection between mitochondrial biology, the autophagosome and the microtubule cytoskeleton in the ageing context employing advanced imaging techniques, cellular and molecular biology, biochemistry and genetics. We aim to provide new explanations for neuronal deterioration in ageing and potential therapeutic strategies.