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RORalpha, the orchestrator of neuron protection

14 December 2009 CNRS (Délégation Paris Michel-Ange)

How do the brain cells called astrocytes ensure the protection of neurons? By studying the protagonists in the protection and satisfactory functioning of neurons, scientists at the Laboratoire Neurobiologie des Processus Adaptatifs (CNRS/UPMC) (1) have found a mechanism that clarifies the role of astrocytes. Crucial to this mechanism, RORalpha protein is revealed as an essential regulator of inflammatory factors. This discovery constitutes a new path for research on novel drugs in the event of cerebral lesions (e.g. neurodegenerative diseases or trauma). These findings were published in the advance edition of PNAS on 1 December 2009.

Astrocytes form part of the glial cells and play a key role in the functioning, well-being and protection of neurons. They react to neuron status and are implicated in the inflammatory response. Inflammation is a complex immune phenomenon that balances the activating and inhibitory actions of a finely-tuned set of molecules. Neuronal inflammation can cause disturbances and hamper the functioning of nerves.

Focusing on glial cells, the scientists hypothesized that there was a contribution of the RORalpha protein in the reaction of these cells to neuronal death. RORalpha is known as a receptor specialized in controlling the expression of genes in the nucleus that exert an anti-inflammatory effect. Until now, it was thought that this protein was exclusively localized in neurons and not in astrocytes.

This discovery thus demonstrates the expression of RORalpha in astrocytes and its role in regulating interleukin-6 (IL-6), an essential mediator of inflammation. In the brain, IL-6 is mainly produced by astrocytes, this production being up-regulated under inflammatory conditions. This molecule has demonstrated neuro-protective properties in several in vivo and in vitro models, but under certain conditions it may also have neurotoxic effects.

The unexpected finding was that RORalpha exerts an ambivalent action on IL-6 production. In astrocytes in an inflammatory situation, RORalpha is up-regulated. It indirectly blocks IL-6 production, preventing any toxicity. However, under normal physiological conditions where the astrocyte is not stimulated, RORalpha activates IL-6 production at concentrations that are beneficial at a basal level. This ambivalence of both RORalpha and IL-6 thus permits astrocytes to react rapidly to attack so as to ensure favorable conditions under all circumstances in the microenvironment of neurons. In vivo, RORalpha is thus the molecular heart of a complex IL-6 regulation mechanism that occurs in the astrocyte to the benefit of neurons.

These results are of particular interest in the context of neuronal death. Indeed, whether this is chronic - as in neurodegenerative diseases - or acute - following a trauma, neuron loss is always associated with a reaction by glial cells. RORalpha is thus a new path that could be followed to search for new drugs for use in these pathological situations.

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