Role of mitochondria in neuronal aging induced by environmental nanoparticles

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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.