In 2018, Dr. Ulises Rodriguez Corona was looking for a new research field where he could apply his knowledge and expertise in the biology of protein production in cells and the genetic instructions that control their behaviour. When he learned of an opportunity to perform high-tech research on protein-protein interactions in RNA metabolism in Dr. Marlene Oeffinger’s lab at the Institute de recherches cliniques de Montréal (IRCM), the chance to move into ALS research more than offset leaving the warm climate in his home country of Mexico.
In his previous work on plants, Dr. Rodríguez Corona realize that specialized fats called phosphoinositides (PIs) interact with proteins found in nuclear speckles — small structures that form and dissolve inside the nucleus of cells. After reading a few scientific papers written by other scientists who had discovered that TDP-43 and FUS, two proteins that behave abnormally in ALS, were also present in nuclear speckles, he wondered if PIs might play a role in ALS as well. Excited to explore this idea further, he worked with Dr. Oeffinger to design an ALS research project.
With a $165,000 Trainee Award from the ALS Canada Research Program, Dr. Rodriguez Corona will explore the normal biology of nuclear speckles to see whether PIs interact with TDP-43 and FUS, changing their function and altering how they move in and out of nuclear speckles.
Most researchers who study TDP-43 and FUS proteins focus on how these two proteins tend to clump in the cytoplasm of motor neurons in ALS. “I’m excited to be looking for clues about what happens in the nucleus,” said Dr. Rodriguez Corona. “If I can show that PIs control the behaviour of these proteins in nuclear speckles, not being able to perform that function properly may be one of the earliest steps in the development of ALS.”
What are nuclear speckles?
If you labelled and coloured in the parts of the cell in science class at school, you may recall that cells contain different structures with odd-sounding names, like the nucleus, lysosomes and mitochondria.
But if you could look at a live cell through a high-powered microscope, you would also see speckles. They form and dissolve in a similar way that oil and vinegar combine into droplets and dissipate in salad dressing. For many years, scientists didn’t know what these speckles were made of. Within the last decade, they discovered that they contain proteins and RNA.
Connecting the dots
For his project, Dr. Rodríguez Corona will investigate the normal biology of nuclear speckles. In his preliminary work, he has already found one PI that interacts with TDP-43 and FUS. TDP-43 and FUS proteins are usually found inside the nucleus of motor neurons, where they play important roles. But in ALS, they behave abnormally by moving out of the nucleus and forming clumps in the cytoplasm. In this work, Dr. Rodríguez Corona will investigate whether this PI, and potentially others, regulate TDP-43 and FUS and are essential for keeping them in the nucleus of healthy cells.
As there is no cure for ALS and there are few available treatment options for most people living with the disease, Dr. Rodríguez Corona is eager to see if his project will reveal some potential new findings to advance ALS research.
“There is still so much to discover about what triggers the development of ALS,” Dr. Rodríguez Corona said. “I’m excited to build on my previous work and explore a totally new idea. If we find that PIs regulate TDP-43 and FUS in nuclear speckles, then normalizing their behaviour may be an interesting avenue of discovery for new treatments for ALS in the future.”