Monday July 09 2007
CEA
Targeting the astrocyte to promote neuron survival
J Neurosci. 27(27) : 7094-7104
CEA
At the Orsay-based Frédéric Joliot Hospital Service (SHFJ), researchers from a joint-run CEA-CNRS team (DSV/ I²BM/MIRCen) working in partnership with a Swiss team has been able to characterize the mechanisms of action of ciliary neurotrophic factor (CNTF)1, a therapeutic candidate for the treatment of Huntington’s disease. These results underline the beneficial role of CNTF-activated astrocytes2, which display functional modifications that promote neuron survival. The work, which has been published in The Journal of Neuroscience, potentially opens up a new field of therapy for neurodegenerative disorders going beyond the neurons to also target astrocytes. [in press]
Huntington’s disease (HD) is a dominant inherited neurodegenerative disorder characterized by motor dysfunction and cognitive deficits. It has a relatively early onset (generally in 30 to 40-year-old subjects), and is fatal within 10 to 15 years. In France, it affects an estimated 6000 people. There is still no effective treatment to slow the course of the disease.
A joint-run team of CEA-CNRS researchers at the SHFJ has devoted years to developing various experimental strategies for treating this disease. One of their approaches drawing on gene therapy consists in causing the brain cells to produce a potentially therapeutic protein by locally injecting genetically-modified viruses containing the protein-coding gene. These viral vectors are allowed to penetrate brain cells in such a way that the genes delivered are directly incorporated into the host-cell DNA. Thus, the neuroprotective effect of the lentivirus and the adenovirus coding for a specific neurotrophic factor, i.e. ciliary neurotrophic factor (CNTF), has been demonstrated in primate, rat, transgenic mouse and cell models of HD.
The team recently tested the hypothesis that one of the targets of CNTF could be astrocytes. These glial cells make up 90% of brain cells, and are involved in a great many functions. They are often activated in disease settings, but little is known of their role in these conditions. These results show that the CNTF expression induced by a lentivirus (lenti-CNTF) in the rat striatum leads to significant changes in astrocyte energy metabolism. The astrocytes in fact draw more heavily on ketone bodies3 and fatty acids, which enables them build a greater resistance to glucose deficiencies and in turn to protect the neurons.
These results potentially open up a new field of therapy for the treatment neurodegenerative disorders, and this research is set to go into to clinical trialling at Henri Mondor hospital.
1. CNTF is a molecule that promotes neuron survival (trophic factor).
2. Astrocytes are start-shaped glial cells found in the brain. The nervous system is built of two kinds of cells: glial cells and neurons. Astrocytes are recognized as active partners to neurons, with which they interact dynamically.
3. Ketone bodies are an importance source of energy for the brain when it is deprived of glucose (the main energy substrate).
Reference:
C. Escartin, K. Pierre, A. Colin, E. Brouillet, T. Delzescaux, M. Guillermier, M. Dhenain, N. Déglon, P. Hantraye, L. Pellerin, G. Bonvento (2007) Activation of astrocytes by CNTF induces metabolic plasticity and increases resistance to metabolic insults. J. Neurosci. (in press).