• From tissue to genes
We are interested in the molecular and cellular mechanisms underlying peripheral neural system (PNS) development, function and disease. The genes that orchestrate the assembly and function of the PNS form a complex network, acting in changing combinations at different developmental stages and under different environmental or disease challenges. In order to gain insights into the molecular networks in which such genes operate and how changes in these networks lead to diseases of the PNS, we are using gene expression profiling techniques to comprehensively analyze the variation of gene expression during normal and disease affected peripheral nerve development. We are concentrating on both the neuronal (dorsal root ganglia neurons) and glial (Schwann cells) compartments of the PNS in order to identify biological pathways important for glial and neuronal maturation and maintenance and interactions between these two inseparable PNS compartments.
• From genes to function
Our gene expression data already taught us that one of the crucial biological pathways important for normal peripheral nerve development and maintenance is the one involved in lipid metabolism. In order to evaluate the role of this pathway in vivo in the PNS we are currently developing and analyzing mouse and rat mutants affecting both lipid and cholesterol metabolism. A combination of molecular, cellular, histological, electrophysiological and behavioral approaches is used to analyze the knockout phenotypes. In addition, we are using an in vitro Schwann cell - DRG neuron co-culture system for prescreening of new candidates generated from our transcriptional analysis.
• From function to disease & back
In humans, the failure to properly develop or maintain PNS neurons or their associated Schwann cells results in a heterogeneous group of disabling peripheral neuropathies. Inherited peripheral neuropathies, collectively referred to as Charcot-Marie-Tooth (CMT) disease, constitute a relatively common set of genetics diseases, with an estimated 1 in 2500 persons affected. We are using identified candidates from our transcriptional and functional analysis of peripheral nerve development and maintenance as biological selection criteria to produce candidate genes for evaluation in different forms of mapped CMTs. Once the causative gene is found we analyze its function in PNS in detail by the above-mentioned in vivo and in vitro approaches. While CMTs are quite common, most of the neuropathies are metabolic and acquired, notably as a sequel of diabetes. Diabetic peripheral neuropathy affects more than half of all individuals with diabetes with a lifetime risk of lower extremity amputations estimated at 15%. We are using rodent models of both type I and II diabetes in order to understand the pathophysiology of this disease.
Representative publications (Complete list of publications (PubMed))
Zenker, J., Stettner, M., Ruskamo, S., Domènech-Estévez, E., Baloui, H., Médard, J.J., Verheijen, M.H., Brouwers, J.F., Kursula, P., Kieseier, B.C., Chrast, R. (2014) A role of peripheral myelin protein 2 in lipid homeostasis of myelinating Schwann cells.
Glia. 62: 1502-12.
Azzedine, H., Zavadakova, P., Bartesaghi, L., Zenker, J., Poirot, O., Bernard-Marissal, N., Arnaud Gouttenoire, E., Cartoni, R., Title, A., Venturini G., Médard, J.J., Planté-Bordeneuve, V., Said, G., Amato, A., Schöls, L., Weis, J., Claeys, K., Stendel, C., Baraban, J., Mundweller, E., Bouslam, N., Stevanin, G., LeGuern, E., Vaz Patto, M., Pinto, N., Lourero, J., Senderek, J., Rivolta, C., Chrast, R. (2013) PLEKHG5 deficiency leads to an intermediate form of autosomal recessive Charcot-Marie-Tooth disease. Hum Mol Genet. 22: 4224-32
Zenker, J., Ziegler, D., Chrast, R. (2013) Novel pathogenic pathways in diabetic neuropathy. Trends Neurosci. 36: 439-49
Zenker, J., Poirot, O., de Preux Charles, A.S., Arnaud, E., Médard, J.J., Lacroix, C., Kuntzer, T., Chrast, R. (2012) Altered distribution of juxtaparanodal Kv1.2 subunits mediates peripheral nerve hyperexcitability in type 2 diabetes mellitus. J Neurosci. 32: 7493-8.
Verdier, V., Csardi, G., de Preux Charles, A.S., Médard, J.J., Smit, A.B., Verheijen, M., Bergmann, S., Chrast, R. (2012) Aging of myelinating glial cells predominantly affects lipid metabolism and immune response pathways. Glia. 60: 751-60.
Cartoni, R., Arnaud, E., Médard, J.J., Poirot, O., Courvoisier, D.S., Chrast, R.*, Martinou, J.C.* (2010) Expression of mitofusin 2R94Q in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A. Brain. 133: 1460-9 (*Equal contribution).
Arnaud, E., Zenker, J., de Preux Charles, A.S., Stendel, C., Médard, J.J., Tricaud, N., Weis, J., Senderek, J., Suter, U., Chrast, R. (2009) SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system. PNAS. 106: 17528-17533.
Nadra, K, de Preux Charles, A.S., Medard, J.J., Hendriks, W.T., Han, G.S., Gres, S., Carman, G.M., Saulnier-Blache, J.S., Verheijen, M.H., Chrast, R. (2008) Phosphatidic acid mediates demyelination in Lpin1 mutant mice. Genes & Dev. 22: 1647-1661.