Belgian-American research team uncovers a new mechanism of neurodegeneration

November 21, 2019

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: Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.

VIB (the Flanders Institute for Biotechnology)

Related RNA Articles from Brightsurf:

A new RNA catalyst from the lab
On the track of evolution: a catalytically active RNA molecule that specifically attaches methyl groups to other RNAs - a research group from the University of Würzburg reports on this new discovery in Nature.

Small RNA as a central player in infections
The most important pathogenicity factors of the gastric pathogen Helicobacter pylori are centrally regulated by a small RNA molecule, NikS.

RNA as a future cure for hereditary diseases
ETH Zurich scientists have developed an RNA molecule that can be used in bone marrow cells to correct genetic errors that affect protein production.

Bringing RNA into genomics
By studying RNA-binding proteins, a research consortium known as ENCODE (Encyclopedia of DNA Elements) has identified genomic sites that appear to code for RNA molecules that influence gene expression.

RNA key in helping stem cells know what to become
If every cell has the same genetic blueprint, why does an eye cell look and act so differently than a brain cell or skin cell?

RNA structures by the thousands
Researchers from Bochum and Münster have developed a new method to determine the structures of all RNA molecules in a bacterial cell at once.

New kind of CRISPR technology to target RNA, including RNA viruses like coronavirus
Researchers in the lab of Neville Sanjana, PhD, at the New York Genome Center and New York University have developed a new kind of CRISPR screen technology to target RNA.

Discovery of entirely new class of RNA caps in bacteria
The group of Dr. Hana Cahová of the Institute of Organic Chemistry and Biochemistry of the CAS, in collaboration with scientists from the Institute of Microbiology of the CAS, has discovered an entirely new class of dinucleoside polyphosphate 5'RNA caps in bacteria and described the function of alarmones and their mechanism of function.

New RNA mapping technique shows how RNA interacts with chromatin in the genome
A group led by scientists from the RIKEN Center for Integrative Medical Sciences (IMS) in Japan have developed a new method, RADICL-seq, which allows scientists to better understand how RNA interacts with the genome through chromatin--the structure in which the genome is organized.

Characterising RNA alterations in cancer
The largest and most comprehensive catalogue of cancer-specific RNA alterations reveals new insights into the cancer genome.

Read More: RNA News and RNA Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to