Project R-14197

The molecular hug between the ER and mitochondria in Charcot- Marie-Tooth disease type 1A (Research)

Protein misfolding is a hallmark of many neurodegenerative diseases. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces ER stress, activating the unfolded protein response (UPR). The ER connects to mitochondria at mitochondria associated membranes (MAM), a specialized platform with an important role in cell homeostasis, including the regulation of calcium signalling, mitochondrial function, the UPR and ER stress. Although their exact role is largely unknown, defective MAM have been demonstrated in several neurodegenerative disorders. Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating disease of the peripheral nervous system and is caused by a duplication of the peripheral myelin protein 22 (PMP22) gene for which no cure exists to date. PMP22 is an aggregation-prone protein situated in myelin produced by Schwann cells. It is not known how the overexpression of PMP22 leads to an abnormal myelin sheath structure and dysfunction in CMT1A. This project aims to explore 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. I hypothesize that PMP22 protein misfolding in CMT1A induces ER stress, leading to the activation of the UPR and Ca2+ signaling pathways, in which MAM play a major role. The outcome of this study, conducted with animal and human models, can reveal important therapeutic targets in CMT1A and other PMP22-related diseases.

01 November 2023 - 31 October 2025