Molecular mechanisms of the axonal degeneration in hereditary neuropathies

Schmidt, Jens; Marquardt, Till (Thesis advisor); Müller, Frank (Thesis advisor); Gess, Burkhard (Thesis advisor)

Aachen (2020)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2020


Charcot-Marie-Tooth disease 1A (CMT1A) belongs to the group of inheritable peripheral neuropathies. The disease is triggered by a duplication of the PMP22 gene. In the course of the disease, a progressive degeneration of motor and sensory nerve fibres occurs. This degeneration can be subdivided into two steps: The first one is the degeneration of the myelin sheath. The second step is the axonal degeneration. With the onset of axonal degeneration, symptoms gradually appear and facilitate the diagnosis in this stage. In this study, the mouse model PMP22-C61 was used to analyse axonal degeneration during CMT1A. This mouse model carries several transgenic copies of the human PMP22 gene and develops symptoms similar to CMT1A. Sarm1 has been described as a major executor of Wallerian degeneration after peripheral nerve injury by NAD+ destruction through its NAD+ase activity. In order to investigate the mechanisms of axonal degeneration, the focus was set on the role of Sarm1 in the axoplasms sciatic nerve axons.Pink1, Parkin, Traf6, BTBD1, BTBD2, BTBD3, and BTBD6 were analysed as possible factors, which might interact with Sarm1. An increased expression level in PMP22-C61 sciatic nerve axoplasms were found for Pink1, Parkin, Traf6, BTBD3, and BTBD6 in vivo. However, no effect on the Sarm1-triggered axonal degeneration was observed by a knock-down of Pink1 in vitro. In contrast to this, both BTBD3 and BTBD6 knock-down resulted in a decrease of the axonal degeneration triggered by Sarm1.In summary, this thesis indicates that Sarm1 plays a role in the axonal degeneration in the course of disease of CMT1A and identified BTBD3 and BTBD6 as two potential factors involved in Sarm1-triggered axonal degeneration with respect to CMT1A.


  • Department of Biology [160000]
  • Chair of Neurobiology [164310]