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Molekulare Neurologie / Hereditäre Neuropathien

Fachliche Zuordnung Molekulare und zelluläre Neurologie und Neuropathologie
Förderung Förderung von 2010 bis 2018
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 163128722
 
Erstellungsjahr 2021

Zusammenfassung der Projektergebnisse

We are studying the molecular mechanisms of altered axon-glia cell interactions in the peripheral nerve system (PNS). We focus on the molecular understanding of Charcot-Marie-Tooth disease (CMT), a group of genetically heterogeneous rare diseases causing a broad clinical spectrum and aim to develop novel therapeutic approaches. This research was made possible by the Heisenberg Professorship which was granted to me by the DFG in 02/2012 until 04/2017. My dual appointment (independant group leader at the Max-Planck Institute of Experimental Medicine, MPIEM and Professor of Neurology (W2) at the University Medical Centre Göttingen, UMG), enables me to translate basic research projects to patients. All aims of my Heisenberg project have been achieved. Highlights from our basic research on PNS glial biology were: that (i) soluble cell derived neuregulin-1 plays a novel role in remyelination. After peripheral nerve injury, axons regenerate and become remyelinated by resident Schwann cells. However, myelin repair never results in the original myelin thickness, suggesting insufficient stimulation by neuronal growth factors. Upon testing this hypothesis, we found that axonal neuregulin-1 (NRG1, a growth factor) type III and, unexpectedly, also NRG1 type I restored normal myelination in the nerve crush model when overexpressed in transgenic mice. Building on these findings we then examined (ii) neuregulin signaling in Pmp22-transgenic rodent models of CMT1A. We found that Schwann cells acquire a persistent differentiation defect during early postnatal development, caused by imbalanced activity of the PI3K-Akt and the Mek-Erk signaling pathways. We demonstrate that enhanced PI3K-Akt signaling by axonally overexpressed neuregulin-1 (NRG1) type I drives diseased Schwann cells toward differentiation and preserves peripheral nerve axons. Notably, in a preclinical experimental therapy using a CMT1A rat model, when treatment is restricted to early postnatal development, soluble NRG1 effectively overcomes impaired peripheral nerve development and restores axon survival into adulthood. These results have been continued with external funding within the ERARE/EJPHD program. Another myelin related project identified (iii) an essential role of transcription factor Smad-interacting protein-1 (Sip1) in remyelination after nerve trauma. In this work, we have also identified novel factors which play an important role in CMT, a disease that commences in early PNS development. Translational and clinical projects are run in parallel in my neurogenetic outpatients clinic at the UMG and included a direct translation from CMT rats to CMT1A patients: Here, we validated the first biomarkers in CMT1A patients which were originally identified in the CMT rat model (iv). We directly validated disease severity markers from the animal model in 46 patients with CMT1A. Our data suggest that the combination of age and cutaneous messenger RNA levels of 2 genes composes a strong indicator of disease severity. This translational approach demonstrates that transcriptional analysis of skin biopsy is suitable to identify biomarkers of Charcot–Marie–Tooth 1A. Moreover, we identified (v) clinical outcome measures with regard to their discrimination of disease severity in 479 CMT1A pateints, the largest described patient’s cohort in Germany. Here, we evaluated primary and secondary clinical outcome measures in CMT1A patients with regard to their contribution towards discrimination of disease severity. These two papers were the basis for novel cutaneous transcripts that serve as diagnostic and prognostic biomarkers of CMT1A disease (vi) that were previously identified in CMT rats. A cluster of eight cutaneous transcripts differentiated disease severity in 266 patients with CMT1A. These projects were extended by the BMBF funded CMT-NET network. In summary, the DFG funded Heisenberg Professorship "Hereditary Neuropathy" together with the support of UMG/MPIEM was the basis to turn Göttingen into a hub for preclinical and clinical research on myelin disorders of the PNS in Germany that has led to numerous collaborations with colleagues in the international CMT community.

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