In 97 per cent of ALS cases and nearly half of cases of frontotemporal dementia, the TDP-43 protein is misplaced to an area outside the cell nucleus of the motor neuron called the cytoplasm. The mislocated TDP-43 may be toxic to motor neurons because it aggregates in the cytoplasm, or because it is no longer performing its normal function in the nucleus.
Scientists have also discovered that mutations in another protein, called hnRNP A1, can cause ALS. In 2018, Dr. Christine Vande Velde discovered that when TDP-43 moves out of the cell nucleus, a new version of hnRNP A1 forms, called hnRNP A1B. Her preliminary work has shown that this new protein may be even more toxic and appears to have a greater ability to form potentially toxic clumps.
With this grant, Myriam Gagné will aim to understand how hnRNP A1B is involved in ALS disease processes by performing cell and mice experiments. She will also validate her findings using ALS tissue samples generously donated by people who had ALS.
Gagné hopes that new insights about the role of hbnRNP A1B in ALS may reveal a better understanding of disease processes and potential targets for new therapies and biomarkers.