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Project

Protein misfolding in Charcot-Marie-Tooth disease type 1A: opening the gates for cathepsin B and peripheral nerve demyelination. (R-12182)

This project describes a novel target in the pathology Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication of the PMP22 gene. CMT1A is a disease of peripheral nerve demyelination, with an altered Schwann cell phenotype and significant changes in the extracellular matrix, the endoneurium. In CMT1A Schwann cells, high levels of misfolded PMP22 aggregates have been observed in association with lysosomes. I aim to show that this leads to rupture of lysosomal membranes and causes the release of cathepsin B, a cysteine protease capable of breaking down components of the Schwann cell basal membrane, including collagen IV and laminin-211. Interestingly, binding of both collagen IV and laminin-211 to Gpr126, a G protein coupled receptor in the Schwann cell membrane, is important to stimulate axonal myelination. Hence, I hypothesize that the degradation of these key basal lamina components leads to a decreased Gpr126 pathway activation which in turn implies a change in gene expression and Schwann cell phenotype, a reduction in myelination, and an altered composition of the endoneurium produced by Schwann cells. My project aims to identify the role of cathepsin B in this disease, in which I am the first to link the Schwann cell defects, demyelination, and the alterations in the endoneurium, both responsible in CMT1A pathology.
Date:1 Nov 2021 →  31 Oct 2023
Keywords:DENTO-MAXILLO-FACIAL, Stem cells
Disciplines:Histology, Neurological and neuromuscular diseases