Winning at basic science: collaboration is critical

30 June 2017

A research team with Ludo Van Den Bosch (VIB-KU Leuven Center for Brain and Disease Research) at its helm has identified a new process that leads to the neurodegenerative brain diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The research uncovered important intra-cellular processes that lead to protein clumping in patients with defects in their C9orf72 genes. These key insights could lead to new treatments that prevent proteins from solidifying. This ground-breaking science would have never been possible, however, without close collaboration across VIB labs, core centers and national boundaries. We asked these VIB researchers to tell us more about the collaboration.

Scientists have known that clumps of proteins – called stress granules – form naturally in neurons, demixing from the watery cytoplasm within cells, and do not lead to disease in normal cells. In this study, VIB’s Steven Boeynaems, Ludo Van Den Bosch, Peter Tompa and colleagues from Belgium and the US, observed that a mutation in the C9orf72 gene causes neurons to produce toxic peptides which bind together spontaneously
and change stress granule processes. This causes stress granules to become more like solids than liquids.

Ludo, can you tell us more about the importance of this key observation?
Ludo: “The finding gives us molecular insight into the formation of protein clumps in these diseases. We believe that this process is an important step that happens just before the irreversible aggregation of these clumps into solids. After they stick together, the damage is permanent and the neuron will not function properly. It’s a pivotal molecular ‘moment’ in the development of the disease.”

A large number of players contributed to the project. Can you give us more details?
Steven: “Scientists from the VIB-KU Leuven Center for Brain and Disease Research, VIB-VUB Center for
Structural Biology, VIB-UGent Center for Medical Biotechnology and several Belgian universities collaborated on the project with scientists from the Howard Hughes Medical Institute, Brown University and Harvard Medical School in the US. Even more, the capabilities of the VIB mass spectrometry, proteomics and bioimaging core facilities were essential to identify the proteins that react to the toxic peptides.”

Steven, you recently presented a TEDx talk on this very basic research. Was it difficult to find the right tone to bring this story to a non-scientific audience?
Steven: “Biophysics can indeed be a challenging subject to present clearly to a lay public. Even so, the phase separation of these ALS-related proteins can easily be compared to processes that we see every day. For example, the demixing of oil and water in your salad vinaigrette is an easily-understood paradigm that demonstrates how two liquids can coexist in a separated state.”

Peter, where does this study fit into the broader spectrum of basic biophysics research?
Peter: “The demixing of proteins that is a hallmark of ALS, called liquid-liquid phase separation, exemplifies similar actions in a great number of physiological and pathological processes, including the formation of stress granules. Our research contributes biophysical and structural experiments to understand these special protein states, potentially contributing to the emerging cell biology paradigm of membraneless organelles.”

Thinking back on the collaboration, were there specific findings that were completely unexpected?
Steven: “Researchers considered the toxic C9orf72 proteins to be aggregation-prone, but we found that, in a test tube setting, they didn’t form solid protein clumps. However, when we added them to cell lysate – a preparation made of destroyed cells – they actually caused the clumping of other proteins. We were very surprised to discover that C9orf72 proteins aren’t aggregation-prone themselves, but instead induce other proteins to aggregate.”

Boeynaems et al., Molecular Cell 2017