Charcot-Marie-Tooth disease (CMT) is an inherited neurodegenerative condition that affects 1 in 2500 individuals. Currently, however, it is still lacking effective treatment options. New research has demonstrated that a class of cytoplasmic enzymes called tRNA synthetases can cause CMT by interfering with the gene transcription in the nucleus. This breakthrough is the result of an international academic collaboration, where scientists from the VIB-UAntwerp Center for Molecular Neurology and the Scripps Research Institute were the driving force. The study was published in the leading journal Nature Communications.
A disease with many faces
Charcot–Marie–Tooth disease (CMT) is a condition that affects the peripheral nervous system. It leads to progressive muscle weakness and loss of sensation in the lower and - later on - upper limbs. It is the most commonly inheritable neuromuscular disorder and, at the moment, remains incurable. The first symptoms can appear both in early childhood or during adult life. Over 90 genes are implicated in the pathology so far and these are involved in a variety of processes. This complexity makes it a difficult condition to study and find a treatment for.
Now, researchers from the VIB-UAntwerp Center for Molecular Neurology and the Scripps Research Institute and their collaborators gained a better understanding of the CMT disease mechanisms that can be applicable for other neurogenerative disorders too.
A problem at the core
The scientists found that in the cell core – the nucleus – of human cell cultures and Drosophila models something went wrong. A major process that happens in the nucleus is the transcription of genetic information encrypted in DNA into RNA molecules, which are then exported in the cytoplasm of the cell and translated into proteins there. The researchers uncovered that an important group of molecules known as aminoacyl-tRNA synthetases – which help in translating RNA into proteins – can also interfere with the transcription of DNA into RNA. This interference was found to be at the core of CMT disease in both fly and cellular models.
Prof. Albena Jordanova explains: “The fundamental message from our work is that components of the translational machinery can function as transcriptional regulators in the nucleus. We demonstrate for the first time that their nuclear role has pathological implications and can cause a neurodegenerative disease. This breaks the current dogmas on the known function of aminoacyl-tRNA synthetases and changes our view on how to study their associated diseases.”
From fly to human?
Dr. Sven Bervoets, first author of the study, explains: “Pharmaceutical inhibition of the tRNA synthetase entry into the nucleus prevented the onset of disease symptoms in our CMT Drosophila model, which could have great implications for CMT patients.” While this work provides hope for CMT patients, many questions remain.
Dr. Bervoets continues. “We will have to investigate the nuclear involvement of all the remaining aminoacyl-tRNA synthetases and identify all their interacting partners in the nucleus. It is also still unclear which other transcription factors are important. Only when these research questions have been addressed, we can start thinking about a therapeutic approach that cures the origin and not only the symptoms of the disease.”
Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy, Bervoets et al., Nature Communications 2019
Questions from patients
A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: email@example.com. Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.
Albena Jordanova (VIB-UAntwerp Center for Molecular Neurology)
Tel.: +32 3 265 10 25
Sooike Stoops (Expert Press and Public Communication VIB)
Tel.: +32 9 244 66 11
Mobile: +32 474 289 252
Note to the editor
When reporting on this news, please mention all partners involved.
When retweet mention us: @VIBLifeSciences @AntwerpU
VIB-UAntwerp Center for Molecular Neurology
Neurodegenerative diseases such as Alzheimer's, epilepsy and muscular disorders are a major challenge for our society. Research at the VIB-UAntwerp Center for Molecular Neurology begins by studying patients and their family members in order to gain new insights into how these diseases start and develop. Thanks to this knowledge, new therapies can be developed.
Basic research in life sciences is VIB’s raison d’être. VIB is an independent research institute where some 1,500 top scientists from Belgium and abroad conduct pioneering basic research. As such, they are pushing the boundaries of what we know about molecular mechanisms and how they rule living organisms such as human beings, animals, plants and microorganisms. Based on a close partnership with five Flemish universities – Ghent University, KU Leuven, University of Antwerp, Vrije Universiteit Brussel and Hasselt University – and supported by a solid funding program, VIB unites the expertise of all its collaborators and research groups in a single institute. VIB’s technology transfer activities translate research results into concrete benefits for society such as new diagnostics and therapies and agricultural innovations. These applications are often developed by young start-ups from VIB or through collaborations with other companies. This also leads to additional employment and bridges the gap between scientific research and entrepreneurship. VIB also engages actively in the public debate on biotechnology by developing and disseminating a wide range of science-based information. More info can be found on www.vib.be.
University of Antwerp
The University of Antwerp is a research university where pioneering, innovative research is conducted at an international level. Research and education are closely linked. Educational innovation is a constant focus, and special care is also taken to welcome and guide each of the 20,000 students spread across our nine faculties. The University of Antwerp is not an island: we build bridges to secondary education, to industry and, by extension, to society as a whole. With over 5,000 members of staff, the University of Antwerp is one of the most important employers in Antwerp, Flanders’ largest city.
More information: www.uantwerp.be