Microtubule decay is a driver of neuronal ageing and a promising target for intervention
Microtubule decay is a driver of neuronal ageing and a promising target for intervention
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DOI：
10.1101/2023.01.11.523590
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发表时间：
2023-01
期刊：
影响因子：
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通讯作者：
Pilar Okenve-Ramos;Rory Gosling;Monika Chojnowska-Monga;Kriti Gupta;Samuel Shields;N. Sánchez-Soriano
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文献类型：
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作者：
Pilar Okenve-Ramos;Rory Gosling;Monika Chojnowska-Monga;Kriti Gupta;Samuel Shields;N. Sánchez-Soriano
自然衰老伴随着运动、感觉和认知功能的下降，所有这些都会影响生活质量。衰老是许多神经退行性疾病的主要风险因素，包括帕金森病和阿尔茨海默病。因此，我们需要更好地了解与年龄相关的神经元衰退的细胞和生理过程。然而，由于使哺乳动物或脊椎动物模型动物老化需要很长时间，因此获得这种理解是一个缓慢的过程。在这里，我们介绍了一个新的细胞模型内果蝇的大脑神经元显示出典型的老化特征，从灵长类动物的大脑，包括轴突sweetness，细胞骨架衰变，减少轴突口径和突触终端产生的形态变化。在苍蝇的大脑中，这些变化发生在短短几周内，非常适合研究潜在的机制。我们观察到神经元微管细胞骨架的衰退明显先于其他衰老标志。我们表明，微管结合因子Tau，EB 1和Shot，是必要的微管维护轴突和突触。它们在衰老过程中的功能丧失引发微管束衰退，随后是轴突和突触的衰退。基因操作，改善微管网络，减缓其他神经元老化的标志，并赋予老年标本的能力，超过年龄匹配的控制。因此，我们的工作表明，微管网络是衰老神经元的关键病变部位，并为改善老年神经元衰退提供了有希望的机会。
Natural ageing is accompanied by a decline in motor, sensory and cognitive functions, all impacting life quality. Ageing is the predominant risk factor for many neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease. We need therefore to gain a better understanding of the cellular and physiological processes underlying age-related neuronal decay. However, gaining this understanding is a slow process due to the long time required to age mammalian or vertebrate model animals. Here we introduce a new cellular model within the Drosophila brain where neurons show typical ageing hallmarks known from the primate brain, including axonal swellings, cytoskeletal decay, a reduction in axonal calibre and morphological changes arising at synaptic terminals. In the fly brain, these changes occur within just a few weeks, ideal to study the underlying mechanisms. We observe that decay of the neuronal microtubule cytoskeleton clearly precedes other ageing hallmarks. We show that the microtubule-binding factors Tau, EB1 and Shot, are necessary for microtubule maintenance in axons and synapses. Their functional loss during ageing triggers microtubule bundle decay followed by the decline in axons and synapses. Genetic manipulations that improve microtubule networks, slow down other neuronal ageing hallmarks and confer aged specimens with the ability to outperform age-matched controls. Our work suggests therefore that microtubule networks are a key lesion site in ageing neurons and offer promising opportunities to improve neuronal decay in advanced age.