Exploring the molecular hug between the ER and mitochondria in Charcot-Marie-tooth disease type 1A

Charcot-Marie-Tooth (CMT) disease is an inherited peripheral neuropathy, affecting 1 in 2,500 people worldwide.

The most common form of the disease, CMT1A, is predominantly demyelinating and is caused by a Peripheral Myelin Protein 22 (PMP22) gene duplication. PMP22 is an aggregation-prone intrinsic membrane protein of the myelin sheath produced by Schwann cells (SC). The structure and function of myelin are disrupted in CMT1A. However, it is unknown how the overexpression of PMP22 contributes to the pathogenesis and therefore, there is no cure available yet.

Due to the overexpression of PMP22, we believe there is an overload of misfolded PMP22 in the endoplasmic reticulum (ER). We hypothesize that this induces ER stress, leading to the activation of the unfolded protein response (UPR) and Ca2+ signalling pathways, mainly regulated by the mitochondria-associated membranes (MAM), where the ER connects to mitochondria. Defective MAM have been demonstrated to play a major role in several neurodegenerative disorders, but their exact function is largely unexplored. Therefore, we aim to investigate the effect of PMP22 overproduction and aggregation in the ER on the UPR response and on MAM-mediated cell signalling and function in CMT1A Schwann cells.

For this project, SC and nerve tissue were isolated from wild-type (WT) or C3-PMP22 mice, an animal model for CMT1A. ER stress was observed in C3 SC and nerve tissue via qPCR with the upregulation of the ER stress-related marker glucose-regulated protein 94 (GRP94). Furthermore, the ER is more densely organized in C3 SC in immunofluorescence stainings. Additionally, mitochondrial changes (e.g. branching) were observed in WT and C3 SC in live-cell imaging experiments using MitoTracker Green. Lastly, we detected ER, mitochondrial and lysosomal changes in CMT1A SC in transmission electron microscopy.

In conclusion, we show in our preliminary data that ER stress, as well as mitochondrial and lysosomal structural changes, are present in CMT1A SC and tissue in gene expression, immunofluorescent and ultrastructural analysis. Future experiments are necessary to indicate how this affects SC myelination, providing important insights into CMT1A and other neurodegenerative, demyelinating, and PMP22-related diseases as well as other forms of CMT.

Authors

Hanne Jeurissen (1)*, Karen Libberecht (1), Tim Vangansewinkel (1), Esther Wolfs (1)

Organisations

Laboratory for Functional Imaging & Research on Stem Cells (FIERCE), BIOMED, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium (1)

Presenting author

Hanne Jeurissen, PhD student, Laboratory for Functional Imaging & Research on Stem Cells (FIERCE), BIOMED, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek
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