Researchers identify clues that link mechanism to the most common hereditary neurological disease

Researchers at the University of Cologne and the Université d’Angers (France) have identified a central mechanism of Charcot-Marie-Tooth disease that could explain the progression of the neurodegenerative disease. They found that mutations in the gene MFN2 that cause the most severe disease subtype 2A (CMT2A) lead to stress in the cells and apoptotic cell death. The results were published in the Journal of Cell Science ("Charcot–Marie–Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death", https://doi.org/10.1242/jcs.263691).

Charcot-Marie-Tooth is the most common hereditary neurological disease. It particularly affects the nerves that control muscles and send sensory information. Patients suffer from muscle atrophy, foot deformations, loss of mobility and sense of touch, and require a wheelchair. Patients with mutations in the Mitofusin 2 (MFN2) protein are particularly severely affected. This protein is located on the surface of mitochondria, the ‘power houses’ of the cell, and controls their shape and stability. Until now, it was unclear how different mutations result in similar disease symptoms.

The team led by Dr. Mafalda Escobar-Henriques (associated to the Center for Molecular Medicine Cologne) at the University of Cologne’s Institute for Genetics has now discovered that different MFN2 mutations in independent human cell lines exhibit a common pattern: they make the cells susceptible to apoptosis, or programmed cell death. Measurements of typical marker proteins showed that the cell death process was activated in all the mutations investigated. Interestingly, the mutations of MFN2 triggered cell death, but cells completely lacking MFN2 or other related proteins were not affected. However, increasing the amount of MFN2 partially attenuated the malfunctions. Experiments on patient cells confirmed these results.

“We were amazed at how clearly and repeatedly we observed the signs of apoptosis in our experiments,” explains Dr. Mariana Joaquim, first author of the study. “We were thus able to show that mutations in MFN2 do not necessarily change the shape of the mitochondria, but definitely contribute directly to cell death. This is a decisive step towards understanding the disease.” Bianca Maria Bulimaga, also first author of the study, adds: “This discovery highlights a novel role of MFN2 variants in disease.”

The results indicate that cell death signalling is a central starting point for better understanding the progression of CMT2A and for developing therapies in the long term. In future, the researchers aim to transfer their findings to neuronal cells in order to decipher the direct link between MFN2 mutations and the death of nerve cells even more precisely.
 

“Who is Mafalda Escobar-Henriques? - Learn more about her research activities 

Original Publication
https://journals.biologists.com/jcs/article/138/18/jcs263691/369280/Charcot-Marie-Tooth-type-2A-variants-of-mitofusin 
Mariana Joaquim*, Maria-Bianca Bulimaga*, Marie A. Mohn, Solenn Plouzennec, Leon Osinski, Selver Altin, Esther Mahabir, Arnaud Chevrollier, Mafalda Escobar-Henriques* (Corresponding author), Charcot–Marie–Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.J Cell Sci (2025) 138 (18): jcs263691. https://doi.org/10.1242/jcs.263691

Authors with CMMC affiliation indicated in bold and first and leading authors are indicated with a star (*) .

Scientific Contact
Dr. Mafalda Escobar
mafalda.escobar[at]uni-koeln.de 

This message has been modified by the CMMC (K. Heber & D. Grosskopf-Kroiher) and is based on the text by the press and communications teams of the University of Cologne (Jan Voelkel, responsible Dr. Elisabeth Hoffmann – e.hoffmann@verw.uni-koeln.de, original version here).