Pathogenesis of inherited neuropathies: implication of components of the innate and adaptive immune system

• Applicant: Professor Dr. Rudolf Martini
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 227548520

Charcot-Marie-Tooth (CMT) type 1 disorders are genetically-mediated neuropathies that are characterized by length-dependent axonal degeneration, muscle atrophy and sensory dysfunction, substantially reducing quality of life. Although more than 80 culprit genes have been identified so far, none of the disorders is treatable. During the last couple of years, our group has shown that in established animal models of CMT, low-grade inflammation driven by CSF-1-activated macrophages substantially amplifies the primarily genetically-mediated disorders and is, thus, a possible access point for therapeutic approaches.During the last funding period, we could unequivocally identify systemic antibodies binding to the diseased nerve fibers of P0het mutants, an established model for CMT1B, as mild modulators of macrophage function in the demyelinating process. This was achieved by an approach ablating the antibody-producing cells genetically, followed by a reconstitution of distinct antibody fractions. Two observations lead to the conclusion that the impact of the antibodies is comparably minor: i) the antibodies are not only mildly, but also transiently involved, i.e., at younger stages, only; ii) in another established model, the antibodies had no detectectable effect on pathogenesis, although decorating diseased nerve fibers. For a continuation of the project, we modified our plans aiming to identify putative major players in the tripartite interaction between mutant Schwann cells, endoneurial fibroblast and pathogenic macrophages. Based on our comprehensive pilot studies, we want in a first approach (Objective 1) to investigate whether the Schwann cell-derived growth factors PDGF-A or -B initiate CSF-1 expression in fibroblasts that activates pathogenic macrophages. For this purpose, we will use cell culture systems and an in vivo treatment approach interfering with PDGF-R. Eventually, sophisticated, timely inducible and cell specific gene knock-out experiments in vivo are planned to identify the responsible PDGF isoforms. Additionally, possible macrophage-derived factors that mediate pathogenic Schwann cell dedifferentiation are of major interest (Objective 2). As candidates for macrophage-driven Schwann cell dedifferentiation, we consider the cytokines TNF-alpha and TGF-beta. By a combination of bone-marrow transfer from cytokine-deficient mutants into myelin mutants experimentally deprived of intrinsic macrophages, we aim to analyse the impact of the cytokine-deficient macrophages on pathogenic Schwann cell dedifferentiation. All in all, our project wants to decipher the major molecular players leading to pathogenic inflammation in CMT mutants, with the aim to develop corresponding treatment strategies.

• DFG Programme: Research Grants