Now, the Albena Jordanova group from the VIB-UAntwerp Center for Molecular Neurology has taken another stride forward in understanding the disease. The researchers used fly models of CMT to uncover new aspects of the disease. We spoke to Albena and Sven Bervoets, the first author of the paper which appeared in Nature Communications.
Where did the idea for this research come from?
Albena: “The idea dates back to 2009 and to my first PhD student here in Antwerp (Ricardo Goncalves). We began unravelling the role of aminoacyl-tRNA synthetases in neurodegeneration. At that time, we had just created the Drosophila model of CMT, the first ever fly model of peripheral neuropathies. Back then we were scanning all old reports about tRNA synthetases and spotted two orphan papers describing their detection in the nucleus. Unexpectedly, we were contacted by our collaborators from the Yang lab at the Scripps Research Institute who had mapped the nuclear localization sequence of tRNA synthetases and asked us whether we would be interested in studying it further. Over the years we nurtured a very fruitful collaboration that yielded ground-breaking findings.”
Is there a specific person who encouraged or inspired you to pursue this question?
Sven: “During my master thesis, performed at the lab of Albena, I already knew I wanted to do a PhD, but I wasn’t sure yet on the topic. The afternoon after I had defended my thesis, I was at a conference on CMT in Antwerp. Here, I met our collaborators from the Scripps research institute for the first time. We started talking about a project they were working on regarding the nuclear function of tRNA synthetases in CMT. Hearing all the preliminary data made me realize that this would be a very innovative research topic. I was hooked immediately.”
At which moment did you realize that this work was going to be so significant?
Sven: “Despite the promising preliminary data, the start of the project was pretty rough as we had to start from scratch and re-generate the proper fly lines. Once the phenotyping of the flies started and we noticed the prevention of the disease phenotypes, we knew we were on the right track. A second realization came once we were able to exclude the protein from the nucleus upon feeding the flies with embelin. Pharmaceutical treatment of our CMT Drosophila model resulted in the prevention of the disease phenotypes, which could have great implications for CMT patients.
"But the molecular mechanisms leading to the disease remain to be elucidated. As a result, no cure exists so far. First, we will have to investigate the nuclear involvement of all the remaining aminoacyl-tRNA synthetases involved in CMT. Next, while the interaction of tyrosyl-tRNA synthetase with one transcription factor has been described, it is unclear which other transcription factors are important. We have to identify all the interacting partners of these synthetases. Only when these research questions have been addressed, we can start thinking about a unified therapeutic approach."
Albena: “The fundamental message from our work is that components of translational machinery can function as transcriptional regulators in the nucleus. We demonstrate for the first time that their ex-translational role has pathological implications and can cause a neurodegenerative disease in humans. This new concept could help to find a cure for CMT as well as other neurodegenerative disorders. I want to see the patients who donated their biomaterials and provided moral support for our studies being cured. Hopefully, my dream comes true!”
How did the collaboration with others improve the scientific research?
Albena: “With the Scripps Research institute, we were able to combine two areas of expertise (molecular biology and disease modeling) into one coherent story. Besides this international collaboration we capitalized on the expertise of two staff scientists in our Center - Bob Asselbergh (microscopy) and Ligia Mateiu (bioinformatics). They became an organic part of the team and enhanced our ability to look critically at the research question from different perspectives. Overall, the success of this work relies on the collaboration efforts where you can maximize people’s skills to advance the research.”
What were the major challenges to overcome?
Albena: “The initial tools and results were not good enough. Sven’s first year of studies was very daunting and the experiments failed frequently. But success consists of going from failure to failure without loss of enthusiasm. The same is true for our struggle with the editors of several candidate journals. Although unpleasant, this experience was very rewarding and inspiring. It helped us to emphasize the true value of our findings and strengthen the evidence for our provocative hypothesis.”
What was the most pleasant aspect of the entire process from study design to publication?
Sven: “Assembling the figures with all the data that you have acquired over the years. You finally start to see the bigger picture and think about the flow of your story.”