Erik Storkebaum, independent Max Planck Research group leader at the Max Planck Institute for Molecular Biomedicine in Münster, Germany, was awarded an MDA research grant totaling $291,000 over three years to study the underlying mechanisms that drive the disease process in Charcot-Marie-Tooth disease (CMT).
Please describe your current research in CMT.
Familial forms of neurodegenerative diseases are caused by mutations in single genes. Some diseases can have different causes — that is, different types of mutations in the same gene can lead to disease. In an individual patient, a single mutation in a neurodegeneration gene can cause disease, but across different patients, different types of mutations in the same disease gene are typically known. Furthermore, for a given neurodegenerative disease, distinct disease genes often encode proteins that function in the same molecular or cellular pathway. It is often unknown whether mutations in ‘related’ or even in a single gene cause disease through a common molecular mechanism, or whether different mutations cause disease through disparate mechanisms. This is a key question from a therapeutic perspective, as common mechanisms may allow for unified therapeutic approaches.
This is also the case for Charcot-Marie-Tooth (CMT) peripheral neuropathy, a disease in which the nerve cables that connect the muscles and skin to the spinal cord degenerate. This leads to muscle wasting, impaired movement, and loss of sensation. Mutations in five distinct genes encoding proteins called tRNA synthetases all cause CMT. These tRNA synthetases play an essential role in the production of proteins. We have recently used the fruit fly Drosophila melanogaster to generate genetic models of these forms of CMT.
Remarkably, the Drosophila CMT models recapitulate key hallmarks of the human disease. In this MDA-funded project, we will use these models to determine whether different mutations across four distinct tRNA synthetase genes cause disease through the same or through disparate molecular mechanisms. In case our results would indicate that all mutations cause disease through a similar molecular mechanism, this may allow a common therapeutic approach for all forms of CMT caused by mutations in tRNA synthetases. Thus, our studies may constitute a first step towards an effective therapy for these diseases, for which currently no FDA-approved drugs are available.
What inspired you to study CMT?
A wonderful aspect of our science is that there is a long-term perspective to help patients affected by incurable diseases. Beyond that, our science is curiosity-driven: We want to unravel the molecular mechanisms that underlie neurodegenerative diseases, in order to understand how they come about and as a first step towards effective therapies.
What is your focus within the neuromuscular disease field, and why is it important?
We work on CMT peripheral neuropathy and on the motor neurodegenerative disease ALS (amyotrophic lateral sclerosis or Lou Gehrig’s disease). We use the fruit fly Drosophila melanogaster as a genetic model for these diseases, as Drosophila is ideally suited to conduct genetic screens, which allow for the identification of disease-modifying genes. We combine Drosophila with mouse genetics, in order to validate whether the identified genes also modify disease in mouse models for CMT or ALS, as mice are the most disease-relevant mammalian model available to date.
The molecular mechanisms underlying CMT and ALS are poorly understood, and both diseases are currently incurable. The rational design of effective drugs against these diseases can only be done if we understand their detailed molecular pathogenesis. Different complementary approaches will likely be required to achieve this goal, and I believe that the combination of Drosophila and mouse genetics could make an important contribution.
What is the expected outcome of this research?
This project will evaluate whether different mutations in four distinct tRNA synthetase genes all cause disease through derailment of the same molecular pathway. If so, this should allow a common therapeutic strategy to be applied to all forms of CMT associated with mutant tRNA synthetases.
Furthermore, our results may give insight into which of two possible therapeutic approaches would be more desirable: increasing the expression of the normal (non-mutant) tRNA synthetase or decreasing the expression of the mutant tRNA synthetase.
What do you feel people impacted by CMT can have the most hope about with respect to research right now?
I feel that it may be possible to identify detailed molecular mechanisms underlying CMT and ALS in the not-too-distant future. These insights may form the basis for the development of effective drugs.
Does your work have any potential implications for other disease fields?
For many neurodegenerative diseases, familial forms are caused by distinct mutations in the same and related disease genes. Therefore, the results of our research, which should elucidate whether CMT-causing mutations in tRNA synthetases cause disease through similar or disparate molecular mechanisms, may create a precedent in the neurodegeneration field and may help and inspire scientists working on other neurodegenerative diseases.
To learn more about how MDA research is accelerating treatments and cures for CMT and ALS, please visit mda.org.