Examining the role of TDP-43 SUMOylation following ALS-relevant stress

In over 97% of people living with ALS, a protein called TDP-43 is found outside its normal location in the cell nucleus, trapped in the cytoplasm where it forms aggregates. While pathogenic variants (mutations) in the TDP-43 gene (TARDBP) cause this dysfunction in a small number of cases, the reason it occurs in most people with ALS remains unknown. One promising area of research focuses on a process called SUMOylation, where small tags called SUMOs attach to proteins and influence how they function and where they go inside cells. In Dr. Maxime Rousseaux’s lab at the University of Ottawa, they found that TDP-43 is SUMOylated in response to cellular stress, which provides greater insights to explore this connection.

This project, led by Veronica Grybas, aims to uncover how stress inside cells might trigger these changes, and whether SUMOylation helps protect TDP-43 from misbehaving under cellular stress. To do this, she has developed a new mouse model that blocks this modification, combined with a known ALS-linked pathogenic variant in the C9orf72 gene to mimic ALS. Veronica will also use human induced pluripotent stem cells (hiPSCs) from people living with ALS to explore whether blocking SUMOylation alters TDP-43’s activity in ways that resemble the disease. Her goal is to uncover how stress and SUMOylation contribute to TDP-43 dysfunction and ALS progression, potentially revealing new targets for treatment.

With expertise in genetics and bioinformatics, Veronica offers a valuable perspective to ALS research, driven by her ultimate goal of building a career focused on the disease. Beyond the lab, she is also deeply engaged in the ALS community, mentoring students, volunteering with SLA Québec, and leading fundraising efforts for the Walk to End ALS, creating meaningful change for people affected by ALS.

The ALS Canada Research Program has made significant investments in understanding the role of stress in ALS, with each funded project bringing us closer to discovering new therapeutic possibilities. This grant expands on the work built by Veronica’s supervisor, Dr. Maxime Rousseaux, who is an established researcher investigating SUMOylation and has been previously supported. Learn more about his lab’s work here.

Funding for Veronica Grybas’ PhD Studentship was made possible through a partnership with Fondation Vincent Bourque, who generously contributed $37,500 to ALS Canada, which Brain Canada matched through the Canada Brain Research Fund (CBRF).