Creation of a predictive model of metabolic changes characteristic of neurodegenerative diseases

Drosophila flies are versatile animal models for the study of genetic mutations in neuronal pathologies. Their small size allows performing in vivo experiments to obtain high resolution nuclear magnetic resonance spectra. Dr. Martine Decoville of CBM, researchers from CEMHTIand ESPCI Paris used spatially-resolved ¹H high-resolution MAS NMR to investigate in vivo metabolite contents in different segments of the fly body. A comparative study of metabolic changes was performed for three neurodegenerative disorders: two cell-specific neuronal and glial models of Huntington disease and a model of glutamate excitotoxicity. These 3 pathologies are characterized by specific and sometimes anatomically localized variations in metabolite concentrations. In two cases, the modifications of ¹H MAS NMR spectra localized in fly heads were significant enough to allow the creation of a predictive model.

Spatially-resolved metabolic profiling of living Drosophila in neurodegenerative conditions using 1H magic angle spinning NMR - Scientific Reports (2020) https://doi.org/10.1038/s41598-020-66218-z

Disturbed expression of autophagy genes in blood of Parkinson’s disease patients

Parkinson's disease is a neurodegenerative pathology characterized by the presence of protein aggregates in the neurons of patients. This neurotoxic accumulation of misfolded proteins could be due to insufficient elimination by autophagic cellular mechanisms. Alain Legrand's group has just published a study highlighting an alteration in the expression of genes coding for autophagy proteins in the blood of patients with Parkinson's disease. This pilot study, carried out in collaboration with the Neurology Department of the Centre Hospitalier Régional d'Orléans (CHRO) and the Fundamental Informatics Laboratory of the University of Orléans (LIFO), shows that defects in autophagic systems that affect the brain of patients can also be detected in peripheral blood cells. These deregulated genes could thus constitute diagnostic markers of Parkinson's disease that can be measured non-invasively after a simple blood test.

El Haddad S. et al, Disturbed expression of autophagy genes in blood of Parkinson's disease patients.  Gene vol. 738 (2020): 144454

Unveiling billion-year old life forms with X-ray vision

An international team of scientists from Brazil, France and Switzerland with financial support from the Serrapilheira Institute and Fapesp, has obtained the most detailed 3D views ever achieved of very ancient traces of life on Earth. The studied microfossils, from the Gunflint Formation, in Canada, are approximately 1.9 billion years old, and are the preserved remains of microorganisms similar to bacteria existing today, but from a period when only microscopic life existed on Earth. Using an advanced imaging method based on synchrotron light, unprecedented details of the shape, composition and preservation of these microfossils was attained. Moreover, in one locality, fossils previously termed “hematite-coated” are revealed to be composed of organic material – invisible in optical microscopy – coated with crystals of the iron oxide maghemite, instead of hematite. This finding challenges our understanding of past life and opens exciting perspectives for the study of even older fossils or future samples returned from Mars.

Maldanis, L., Hickman-Lewis, K., Verezhak, M. et al. Nanoscale 3D quantitative imaging of 1.88 Ga Gunflint microfossils reveals novel insights into taphonomic and biogenic characters. Scientific Reports 10, 8163 (2020). https://doi.org/10.1038/s41598-020-65176-w

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3D observation of microfossils

Organometallic networks for the near-infrared emission of lanthanides

Researchers from the group "Luminescent lanthanide compounds, spectroscopy and optical bioimaging" and the University of Pittsburgh (USA) have designed a rigid three-dimensional chemical system of organometallic network type composed of lanthanides and organic molecules. A major originality of this work is based on the use of the cavity of this network to generate in situ the molecular system sensitizing the lanthanide cations. This new approach has the advantage, among other things, of allowing the excitation length to be controlled. This network is well suited to the real conditions of optical biomedical imaging on living cells.

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These researches have been published on Journal of American Chemical Society

Patrick F. Muldoon, Guillaume Collet, Svetlana V Eliseeva, Tian-Yi Luo, Stephane Petoud, and Nathaniel L Rosi. Ship-in-a-bottle preparation of long wavelength molecular antennae in lanthanide metal-organic frameworks for biological imaging. J. Am. Chem. Soc. (2020) 142, 8776-8781 - doi : 10.1021/jacs.0c01426

Manganese: A double agent for imaging ?

Gadolinium (Gd3+) complexes have been used as MRI contrast agents for 35 years, but recently the safety of some was questioned. The replacement of Gd3+ by manganese (Mn2+), a biogenic metal, would enable safer complexes.

Nevertheless, the Mn2+ has to be chelated by complexes exhibiting high thermodynamic stability and kinetic inertness (to guarantee that the Mn is not released in vivo) and with a water molecule directly coordinated to the metal, essential for a good MRI efficiency. Combining these two properties is a chemistry challenge.

The “Metal complexes and MRI” team of CBM and their collaborators from IPHC (Strasbourg) have synthesized and studied a bispidine ligand, a molecule which cavity is well adapted for Mn2+ complexation. This Mn2+ complex has an excellent kinetic inertness and its MRI efficiency was validated by preclinical studies.

52Mn is an emergent radionuclide for positron emission tomography (PET). Mn2+ is the only metal enabling both MRI and PET imaging. The use of 52Mn is nevertheless limited by its low availability and lack of appropriate ligand.

For the first time in France, 52Mn was produced at the Orléans’ cyclotron, and 52Mn-bispidine was successfully obtained.

Overall, bispidine is a very promising ligand for the Mn2+ complexation, for MRI and PET. Due to its outstanding kinetic inertness, in vivo use of Mn2+ without toxicity risk can be anticipated.

 

See the news on the website of the CNRS Institute for Chemistry.

 

Eva Toth, Daouda Ndiaye, Maryame Sy, Agnès Pallier, Sandra Même, Isidro de Silva, Sara Lacerda, Aline M. Nonat, Loïc J. Charbonnière Unprecedented kinetic inertness for a Mn2+‐bispidine chelate: a novel structural entry for Mn2+‐based imaging agents - Angewandte Chemie, 2020, https://doi.org/10.1002/anie.202003685

Metallomics in geological time: trace element biosignatures evidence the influence of ocean chemistry on Earth’s earliest ecosystems

We used a combination of techniques: microbeam particle-induced X-ray emission spectroscopy (PIXE), carbon isotope geochemistry and electron microscopy. This has allowed us to discover trace element signatures of life in 3.33 billion-year-old rocks from South Africa. These signatures support a long-standing hypothesis that biological dependency on trace elements results from the enrichment of these elements in the metal-rich, hydrothermally influenced habitats of early life.

We approached this challenge through the biological concept of the metallome, which refers to the entirety of the inorganic species (metal and metalloid) within a cell. Although the genome and proteome do not survive fossilisation over billions of years, it is probable that metal concentrations within carbonaceous materials could do so, and indeed we found this to be the case in numerous carbon-rich microstructures from the Josefsdal Chert.

We found that a range of elements crucial to anaerobic microbes, including Fe, V, Ni, As and Co, were enriched within carbonaceous material characterised by negative carbon isotope signatures indicating biological origins.

Palaeo-metallome compositions could be used to deduce the metabolic networks of Earth’s earliest ecosystems and, potentially, as a biosignature for the evaluation of organic materials found on Mars.

The article “Metallomics in deep time and the influence of ocean chemistry on the metabolic landscapes of Earth’s earliest ecosystems” released March 18th in Scientific Reports.

Contact: keyron.hickman-lewis@cnrs.fr; frances.westall@cnrs.fr

 

Numerical simulation to better select drugs before clinical trials

Chemists from the Institute of Organic and Analytical Chemistry (ICOA, CNRS / University of Orléans) and the Center for Molecular Biophysics (CBM, CNRS) propose a new in silico model, which describes the duration of interactions between a molecule and its biological target. Published in the Journal of Chemical Information and Modeling, this work has successfully predicted effects on a protein linked to certain cancers and helps to reduce doses and thus toxicity.

See the communication from the CNRS Institute for Chemistry