$125,000 awarded to Dr. Christine Vande Velde, Centre de recherche du CHUM at Université de Montreal, in collaboration with Dr. Marlene Oeffinger, Institut de recherches cliniques de Montréal (IRCM)
TDP-43 is a protein that behaves abnormally in the motor neurons of 97 per cent of people with ALS. It is usually found in the nucleus, but in people with ALS, it becomes trapped outside in the cytoplasm where it forms aggregates. Previous work in the Vande Velde lab showed that the mislocalization of TDP-43 to the cytoplasm results in decreased levels of another protein, called G3BP1.
G3BP1 is an essential protein for the formation of stress granules, which are protective structures that healthy cells make when they are exposed to environmental stress. Stress granules protect vulnerable RNA (molecules that translate genetic instructions and oversee protein production) from becoming damaged.
It remains unclear whether the role of G3BP1 in stress granule dynamics is the main contributor to it’s influence on motor neuron health, or whether it has additional functions in key cellular pathways. Preliminary work suggests a role for G3BP1 in additional pathways, as studies examining its sister protein G3BP2, which has a similar function in stress granule dynamics, reveal that when G3BP1 levels are reduced G3BP2 cannot fully compensate for the loss.
With this award, Dr. Vande Velde seeks to understand the function of G3BP1 in a more holistic way. The team will define and compare the protein interaction network for both G3BP1 and G3BP2 in neurons. They will also examine the role both proteins play in RNA degradation within cells and how this influences ALS disease processes. Finally, they will explore whether a unique, recently understood biology in ALS, called cryptic exon inclusion, is responsible, at least in part, for the loss of G3BP1 at the RNA level.
Ultimately, the results from this study will help researchers more fully understand the wide array of cellular functions G3BP1 is involved in, and how these differ compared to its sister protein G3BP2. The proposal builds on prior foundational work and will influence ongoing studies aimed at restoring G3BP1 levels as a treatment strategy for ALS.