Role of mitochondria in neuronal aging induced by environmental nanoparticles

衰老的特点是细胞功能和机体健康状况逐渐下降，神经退行性疾病、发展和死亡的风险增加。衰老过程的一个潜在原因是氧化损伤的逐渐积累。线粒体功能障碍在介导和放大推动衰老过程的氧化应激方面发挥着至关重要的作用，它也与阿尔茨海默病(AD)或帕金森病(PD)等与年龄相关的神经退行性疾病有关。有趣的是，衰老过程伴随着应激抵抗力的下降，包括对环境污染物的耐受性，这可能在发生神经退行性疾病的易感性改变中发挥作用。因此，近年来，接触纳米颗粒已成为一个日益令人担忧的问题。以前已经注意到，这些颗粒性环境毒物可能以线粒体为靶标，并损害其功能。然而，除了稀有的例子(如鱼藤酮、百草枯)外，哪些污染物是重要的，并能够改变衰老过程，并通过影响线粒体功能促进神经退行性疾病的发展，这些仍然在很大程度上未知。与现有技术相比，这一建议的创新之处在于其独特的方法，利用线虫秀丽线虫(C.elegans)作为筛选工具，识别和表征能够加速体内年龄相关神经退化发展的环境毒物的影响。为此，我们将使用野生型和易聚集疾病模型，确定选定类型的环境相关纳米颗粒对线虫不同年龄相关神经肌肉终点的影响。影响线虫衰老的纳米颗粒将被用于研究它们对从野生型或AD小鼠获得的啮齿动物原代神经元培养中神经退化相关病理的影响。然后，我们将评估线粒体氧化还原稳态的改变是否是纳米颗粒诱导线虫和初级啮齿动物神经元变性的分子机制。因此，我们将利用新开发的疾病模型和方法，使用跨学科的方法来深入了解环境因素在衰老过程中的作用以及在与年龄相关的神经退行性疾病的发展中的作用，并指出新的潜在疾病风险因素和有针对性的治疗(和预防)方法，以摧毁人类与年龄相关的疾病，这些疾病迄今尚未有效治愈，并给我们的社会带来巨大的经济负担。

Aging is characterized by a progressive decline in cellular functions and organismal fitness and by an increased risk of neurodegenerative diseases development and death. One potential cause of the aging process is the progressive accumulation of oxidative damage. Mitochondrial dysfunction play a crucial role in mediating and amplifying the oxidative stress that drives the aging process and it is also associated with age-related neurodegenerative disorders such as Alzheimer's disease (AD) or Parkinson's disease (PD). Interestingly, the aging process is accompanied by a decline in stress resistance including tolerance to environmental contaminants, which can play a role in altered susceptibility to develop neurodegenerative diseases. Herein, exposure to nanoparticles has become an increasing matter of concern in recent years. The possibility that these particulate environmental toxicants may target mitochondria and impair their function has been noted previously. However, which contaminants are important and are able to alter the aging process and to contribute to the development of neurodegenerative diseases by affecting mitochondrial functionality, are besides scarce examples (e.g. rotenone, paraquat) still largely unknown. The innovative nature of this proposal compared to the state of the art is its unique approach to exploit the nematode Caenorhabditis elegans (C. elegans) as a screening tool to identify and characterize the effects of environmental toxicants able to accelerate the development of age-associated neurodegeneration in vivo. To this end, we will determine the effect of selected types of environmental related nanoparticles on different C. elegans age-associated neuromuscular end points, using both wild-type and aggregation-prone disease models. The nanoparticles impacting on C. elegans aging will be then used to study their effects neurodegeneration-associated pathologies in rodent primary neuronal cultures obtained from wild-type or AD mice. We will then assess whether alteration of the mitochondrial-redox homeostasis underlay the molecular mechanisms behind nanoparticle-induced neuronal degeneration in C. elegans as well as in primary rodent neurons.Taking advantage of newly developed disease model and methods we will thus use an interdisciplinary approach to gain insights into the role of environmental factors in the aging process as well as in the development of age-associated neurodegenerative diseases, and to indicate new potential diseases risk factors and targeted therapeutic (and preventive) approaches for devastating human age-associated disorders, which to date have ineffective cure and represent a huge economical burden for our society.