About 75% of the genes involved in human diseases are also found in fruit flies. This makes them an excellent model for studying how certain diseases develop and progress. For her PhD research, Been used fruit flies to investigate, among other things, how a specific form of ALS develops. ‘This is a rare hereditary variant of ALS caused by mutations in the FUS gene (fused in sarcoma),’ she explains. ‘This variant often affects teenagers, whereas most people who develop ALS are over 40.’
Protein Clumps
Been suspected that part of the FUS protein triggers the formation of protein droplets in cells, which later clump together and fail to dissolve in ALS patients. Previous studies had already shown that such clumps are found in the brains of deceased ALS patients. ‘These droplets form in everyone who is under stress, but when the stress subsides, they normally disappear again,’ Been says. ‘In ALS patients, this process works differently.’
By studying how this process occurs in fruit flies, she was able to draw conclusions about how it might work in humans. Her hypothesis turned out to be partly correct. ‘The FUS protein in fruit flies lacks the section of the human FUS protein that is necessary for forming protein droplets. When we inserted this human segment into the fly’s FUS gene, we observed the formation of droplets and clumps similar to those seen in ALS. We also noticed behavioral changes typical of ALS — for example, the flies were less able to climb up a test tube.’
Towards a Cure
The clumping of protein droplets may therefore play a key role in the development of ALS. ‘Of course, this still needs to be studied in humans,’ Been cautions. ‘The challenge is that ALS is often already advanced by the time symptoms appear. So, except in hereditary cases, it’s difficult to know who will develop the disease.’
More research is needed, but these findings could help us better understand ALS. ‘Ultimately, putting together all the small pieces of the puzzle could lead us toward a cure,’ she says.
Want to know more about Marije Been’s research? Watch her video from the University of the Netherlands (in Dutch, with English subtitles).