Project Details
Projekt
Function of the peripheral myelin protein 22 kDa (PMP22) and its role in the pathogenesis of Charcot-Marie-Tooth disease 1A (CMT1A)
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 456979405
Overexpression of PMP22, an abundant tetraspan transmembrane protein in the myelin sheaths of the peripheral nervous system (PNS), causes the most common hereditary neuropathy, Charcot-Marie-Tooth disease 1A (CMT1A). With the help of transgenic rodent models, we uncovered an inhibition of the PI3K/Akt signaling pathway in Schwann cells as an immediate downstream event following Pmp22 overexpression. The function of PMP22 is not known, but mounting evidence points to a general growth-inhibitory role of PMP22. In a combined cell biological and biochemical approach, we will explore possible growth-signaling related functions of PMP22, and work out further details of the functional interaction between PMP22 and the signaling apparatus. With the help of conditional mouse mutants, we will examine a role of PMP22 in promoting PTEN, the major inhibitor of PI3K/Akt signals, as well as other possible functional interactions of PMP22 with growth- and adhesion signaling. By applying super-resolution microscopy and CRISPR-Cas9 aided affinity labeling, we will be able to map these events on the highly polarized myelinating Schwann cell at the nanoscale level, and thereby learn how PMP22 contributes to a loss of this polarized organization in CMT1A. To determine the molecular interactions that allow PMP22 to execute its function, we will biochemically dissect complexes of PMP22. Starting from a pool of candidate binding partners that we have generated and will further expand during the project by using unbiased approaches, we will initially test direct interaction of PMP22 and adhesion associated proteins: periaxin, non-muscular myosin IIa, vimentin, talin. We will then scrutinize our results by reconstituting molecular interactions of PMP22 in vitro and capturing them in situ in peripheral nerve, thereby essentially contributing to a much-needed molecular understanding of PMP22 function and the molecular pathogenesis of CMT1A. Our research project will thus pave the way for novel therapeutic approaches.
DFG Programme
Research Grants
