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Vieillissement et maladies neurodégénératives : nouvelles contraintes apportées par la métallomique

Abstract : Characterized by the progressive and irreversible decline of vital biological functions, ageing is a complex biological process that often comes with neurodegenerative disorders. In 2050, more than 1.5 billion elderly are expected in the world. Improve the quality of life of these ageing people is therefore a major challenge for our society. Still poorly known, the progressive degradation of the metallome is asscociated with ageing and neurodegenerative diseases development and is probably one of their causes. The objective of this study is to better characterize the metallome evolution in two animal models over time i.e. the mouse and the worm as well as in human affected by amyotrophic lateral sclerosis (ALS). To do this, we analyzed twenty trace and major elements as well as the isotopic compositions of copper (δ65Cu) and zinc (δ66Zn) of mouse organs, different strains of nematodes, and human cerebrospinal fluid (CSFs).The analysis of mouse organs shows that important chemical and isotopic changes develop in the body over time, each organ having its own elemental and isotopic signature. For example, we observe an increase of the Cu concentration in the brain associated with a decrease of the δ65Cu in the liver over time. Based on the analysis of metabolomic parameters and the use of isotopic mixings, we show that these variations may be explained by major physiological and metabolic dysfunctions, such as the deregulation of hepatic fluxes and/or the degradation of the blood-brain barrier with age. This suggests that the temporal analysis of the metallome could be used as a potential marker of the biological age.The analysis of nematodes revealed that long-lived animals differ from short-lived nematodes by an early-age decrease in their Cu isotopic composition and Cu concentration. The temporal monitoring of these biomarkers could therefore be used to detect premature ageing conditions.Finally, the analysis of CSFs of patients with amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disease for which there is currently no reliable biomarker or treatment, shows that ALS patients have a higher δ65Cu compared to healthy subjects and Alzheimer’s disease patients. This feature, offering new perspectives to identify ALS-specific biomarkers, may be explained by the formation of toxic protein aggregates in the brain.
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https://tel.archives-ouvertes.fr/tel-01941713
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Submitted on : Sunday, December 2, 2018 - 1:06:47 AM
Last modification on : Tuesday, February 18, 2020 - 3:54:02 PM
Long-term archiving on: : Sunday, March 3, 2019 - 12:31:13 PM

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  • HAL Id : tel-01941713, version 1

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Lucie Sauzéat. Vieillissement et maladies neurodégénératives : nouvelles contraintes apportées par la métallomique. Médecine humaine et pathologie. Université de Lyon, 2018. Français. ⟨NNT : 2018LYSEN005⟩. ⟨tel-01941713⟩

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