Researchers Uncovered a New Mechanism of Neurodegeneration
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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."
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