Onward to new therapies for neurodegenerative diseases ALS and FTD

20 August 2016
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal, adult-onset neurodegenerative disorders. The group of Ludo Van Den Bosch and Wim Robberecht (VIB-KU Leuven) has discovered profound new insights into the causes of these diseases that will drive future research and hopefully lead to more effective treatments.

Under the supervision of professors Ludo Van Den Bosch and Wim Robberecht, PhD students Steven Boeynaems and Jolien Steyaert, lab technician Wendy Scheveneels and Dr. Elke Bogaert investigated the behaviors and characteristics of the proteins that cause ALS and FTD. This work was made possible by a collaboration between a large number of VIB groups, including the groups of Kevin Verstrepen, Patrick Callaerts, Christine Van Broeckhoven and SWITCH. As a result of the project, two papers have been published in the journals Nature Neuroscience and Scientific Reports.

What is the most important finding of this research?
Ludo: “It is the first time that we see an important role for inter-cell transport in the most important genetic forms of ALS and FTD. Even more, these insights have a solid basis, since they come from four different scientific angles. It is an important next step in our understanding of these terrible diseases.”

Do the findings of your research suggest new treatments for these diseases?
Wim: “Recently, two other papers were published in Nature using fruit flies with these genetic repetitions that also generated toxic proteins. The studies showed that problems in the transport system within cells is important in genetic ALS and FTD. With this in mind, changing the processes that govern this transport system could be a promising new therapy for these diseases.”

Can you describe the biggest challenges you encountered during this project?
Wendy: “The time pressure on this project was high and therefore we needed to be ready to switch rapidly between different approaches and techniques. To be able to finish this study in one year was experimentally challenging, but highly rewarding.”

How did you experience the dynamics within your own research group?
Jolien: “We work with fruit flies to study different genes involved in neurodegeneration. My PhD project focusses on a different gene as the one described in this paper, nevertheless both projects benefited from each other. It was an opportunity to be involved in this nice research project. The scientific discussions that we had in our team were always in an open atmosphere and very interesting.”

How did all these teams get involved in this study?
Steven: During my master training in the lab of Kevin Verstrepen (VIB/KU Leuven) I learned more about “junk” DNA and yeast research. I started my PhD in Ludo’s and Wim’s lab on the newly discovered repeat expansions in ALS and FTD. Here the idea originated of using the genomic toolbox of yeast to get insights in human disease. We teamed up with Kevin and started generating yeast disease models which we could use for genome-wide screening. At the same time, we generated fly models for these repeat expansions with Patrick Callaerts (VIB/KU Leuven). We found out that the group of Aaron Gitler at Stanford University was pursuing similar objectives. Hence, we decided to divide the work load and focus ourselves on the fly work, whereas the Gitler group would build further on our initial yeast data. Compellingly, the modifiers that we found in yeast were nicely validated in our fly genetic screen. In the last stage of the project, we used the expertise of the SWITCH lab (VIB/KU Leuven) and the Van Broeckhoven lab (VIB/Antwerp University) to check whether our identified modifiers could be important to the human disease, which turned out to be the case.

Was it a challenge collaborating with so many people and groups?
Elke: “It has been a great experience collaborating with so many top labs. The expertise brought in by each and every collaborator was pivotal in finishing this study. We had tremendous benefits from the open research environment that VIB has created as we experienced that the approachability of the different teams was great, even for PhD students and Post Docs. The smoothness of this collaboration made it possible to complete the story from start to finish in one year. This was crucial to keep up with two competing American groups.”

Yeast paper: Jovičić et al., Nat Neurosci. 2015
Drosophila paper: Boeynaems et al., Scientific Reports 2016


About ALS and FTD
In ALS, parts of the brain and spinal cord that are involved in movement and motor control are affected, causing muscle weakness and paralysis. In FTD, neurons in the brain degenerate which leads to behavioral, personality and language disturbances. ALS and FTD are the extremes of one disease spectrum. The most important genetic cause of ALS and FTD was discovered in 2011: a mutation causing the repetition of a piece of non-coding or “junk” DNA in a gene with an unknown function, called C9orf72. Proteins encoded by this junk DNA are potentially toxic but how these proteins cause toxicity is not yet completely understood. Using genetic tools available in yeast and fruit flies, Ludo’s research team confirmed that two of these proteins hijack the nucleocytoplasmic transport system, causing proteins to mislocalize within the cell.

Jolien Steyaert, Elke Bogaert, Steven Boeynaems, Wendy Scheveneels and Ludo Van Den Bosch