CE34 - Contaminants, écosystèmes et santé

Mechanisms of environmental metals induced cytoskeletal synaptic toxicity: from super-resolution imaging to molecular identification – SuperResMetalToxSyn

Mechanisms of environmental metals induced cytoskeletal synaptic toxicity: from super-resolution imaging to molecular identification

Environmental exposure to neurotoxic metals is a global health concern affecting millions of people worldwide. Four metals (arsenic, lead, mercury and cadmium) have been listed among the ten chemicals of major public health concern by the World Health Organization. Manganese and uranium are two other elements of growing concern. They all cause neurotoxic effects.

One solution to tackle this global issue is to better understand the molecular mechanisms involved in the neurotoxicity of environmental metals and to design targeted prevention strategies

Recent research works have emphasized the consequences of extended low-level exposures to large populations. It is increasing recognized that the onset and progression of many age-related neurological diseases, including Alzheimer’s disease, may be triggered and/or accelerated by environmental exposure to metal contaminants. However, despite decades of research, the underlying molecular mechanisms involved in neurodegenerative diseases remain poorly understood.<br />We propose to assess a new mechanism for metal-induced neurotoxicity based on the direct interaction of metals with the synaptic cytoskeletal architecture and occurring at environmentally relevant concentrations. Such interaction would cause the disorganization of the synaptic structure, possibly by competition with essential metals binding-sites, resulting in synaptic impairments and neurological dysfunctions. We will characterize at the cellular and molecular levels the interactions of known environmental neurotoxic metals (arsenic, cadmium, lead, manganese, mercury, uranium) with synaptic cytoskeleton proteins (tubulin, actin), and will evaluate prevention strategies involving essential elements (copper and zinc).<br />The project has 4 aims:<br />- The assessment of environmental metals synaptic toxicity on primary hippocampal neurons;<br />- The correlative nano-imaging of metals and cytoskeleton proteins in synaptic compartments;<br />- The molecular characterization of metal-binding to cytoskeleton proteins;<br />- The assessment of protective effects of essential metals against synaptic toxicity.<br /><br />Our project applies preferentially to the aetiology of Alzheimer’s disease because of the experimental cellular model chosen, hippocampal neurons, but the suggested mechanisms are likely to be involved in other neuro-pathologies such as autism and attention deficit disorders, depending on the period of exposure over the lifetime. We expect to show for the first time ever the presence of environmental metals in synapses and to describe the consecutive impairment of synaptic structures. These striking results will contribute to focus the attention of the scientific community, the public authorities and of the citizens on such environmental hazards. The comparison of different metals should help prioritize preventive and regulatory interventions.

This interdisciplinary study will benefit from the complementarity of 3 research teams experts in: metal neurotoxicology (CENBG), neurobiology of synapses (IINS), metal-protein interactions (BIAM); and from the access to an outstanding instrumentation: synchrotron XRF (X-ray fluorescence) nano-imaging of metals correlated to STED (stimulated emission depletion) super-resolution microscopy of proteins, and native ESI-MS (electrospray ionization mass spectrometry) analysis of metal binding to proteins. Primary rat hippocampal neurons will be used as experimental model.

In progress.

In progress.

In progress.

Environmental exposure to neurotoxic metals is a global health concern affecting millions of people worldwide. Four metals (arsenic, lead, mercury and cadmium) have been listed among the ten chemicals of major public health concern by the World Health Organization. Manganese and uranium are two other elements of growing concern. They all cause neurotoxic effects. Recent research works have emphasized the consequences of extended low-level exposures to large populations. It is increasing recognized that the onset and progression of many age-related neurological diseases, including Alzheimer’s disease, may be triggered and/or accelerated by environmental exposure to metal contaminants. One solution to tackle this global issue is to better understand the molecular mechanisms involved in the neurotoxicity of environmental metals and to design targeted prevention strategies. However, despite decades of research, the underlying molecular mechanisms involved in neurodegenerative diseases remain poorly understood.
We propose to assess a new mechanism for metal-induced neurotoxicity based on the direct interaction of metals with the synaptic cytoskeletal architecture and occurring at environmentally relevant concentrations. Such interaction would cause the disorganization of the synaptic structure, possibly by competition with essential metals binding-sites, resulting in synaptic impairments and neurological dysfunctions. We will characterize at the cellular and molecular levels the interactions of known environmental neurotoxic metals (arsenic, cadmium, lead, manganese, mercury, uranium) with synaptic cytoskeleton proteins (tubulin, actin), and will evaluate prevention strategies involving essential elements (copper and zinc).
This interdisciplinary study will benefit from the complementarity of 3 research teams experts in: metal neurotoxicology (CENBG), neurobiology of synapses (IINS), metal-protein interactions (BIAM); and from the access to an outstanding instrumentation: synchrotron XRF (X-ray fluorescence) nano-imaging of metals correlated to STED (stimulated emission depletion) super-resolution microscopy of proteins, and native ESI-MS (electrospray ionization mass spectrometry) analysis of metal binding to proteins. Primary rat hippocampal neurons will be used as experimental model.
The project has 4 aims:
- The assessment of environmental metals synaptic toxicity;
- The correlative nano-imaging of metals and cytoskeleton proteins in synaptic compartments;
- The molecular characterization of metal-binding to cytoskeleton proteins;
- The assessment of protective effects of essential metals against synaptic toxicity.
Our project applies preferentially to the aetiology of Alzheimer’s disease because of the experimental cellular model chosen, hippocampal neurons, but the suggested mechanisms are likely to be involved in other neuro-pathologies such as autism and attention deficit disorders, depending on the period of exposure over the lifetime. We expect to show for the first time ever the presence of environmental metals in synapses and to describe the consecutive impairment of synaptic structures. These striking results will contribute to focus the attention of the scientific community, the public authorities and of the citizens on such environmental hazards. The comparison of different metals should help prioritize preventive and regulatory interventions.

Project coordination

Richard Ortega (CENTRE D'ETUDES NUCLEAIRES DE BORDEAUX GRADIGNAN)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CENBG CENTRE D'ETUDES NUCLEAIRES DE BORDEAUX GRADIGNAN
IINS INSTITUT INTERDISCIPLINAIRE DE NEUROSCIENCES
BIAM Institut de biosciences et biotechnologies d'Aix-Marseille (UMR 7265)

Help of the ANR 429,110 euros
Beginning and duration of the scientific project: January 2022 - 36 Months

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