U of A lab receives important funding towards determining cause of ALS

Division of Neurology professor Valerie Sim. Photo supplied.

Valerie Sim, in collaboration with Divisions of Neurology and Neuropathology teammates Sumit Das and Sanjay Kalra, has been awarded a 2023 Discovery Grant from ALS Canada and Brain Canada.

Amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, leads to progressive degeneration of nerve cells in the spinal cord and brain. There is no cure.

The funding will help Sim and her University of Alberta lab redirect their prior work studying prion diseases toward determining the cause of ALS and finding new treatments.

“Beyond my research life, I am also a clinician, and I see and diagnose people with ALS. Like prion disease, it is a devastating diagnosis, and if I can direct my knowledge and energy towards finding a way to stop this horrible disease, then I am honoured to do so,” says Sim.

The ALS Canada-Brain Canada Discovery Grants provide the research community with crucial funding for projects focused on ALS and related neurological diseases.

Sim’s lab has more than 15 years of experience studying prion diseases, which are caused by misfolded proteins that self-template, clump together, and spread through the brain like dominoes, killing brain cells. Work by other groups has demonstrated that ALS has prion-like features as well, with misfolded proteins that can spread through the spinal cord and brain, killing the cells responsible for movement.

“Given the experience and tools we have for studying prion proteins, we’re excited to apply the same approach to ALS, looking to see whether different shapes of the protein TDP-43 are responsible for the different patterns of ALS disease,” says Sim.

Current evidence shows this protein plays a major role in causing ALS.

The grant will support a master’s student project in which Sim’s lab will take samples from ALS-affected brains, donated by patients who died from different forms of ALS, and isolate the full range of TDP-43 protein sizes and shapes from different brain regions. 

“We predict that certain ALS subtypes and brain regions will have smaller or larger clumps of TDP-43 and that different shapes of TDP-43 may be more or less efficient at triggering the domino effect of more misfolding. The goal is to link the size and shape of TDP-43 misfolded clumps with the pattern of disease seen in the patient,” says Sim.

While the project has only just started, the lab has already isolated different-sized clumps of TDP-43 from human brains affected by another related disease associated with the buildup of TDP-43 clumps. 

“Once we have perfected our isolation protocol on these non-ALS brains, we will start using the more precious ALS samples,” says Sim.

Sim is optimistic about the new focus on ALS.

“I have always been fascinated by the idea that a protein alone can be infectious. My work to date has largely been in prion diseases. However, with all the growing evidence for prion-like infectious proteins causing other neurodegenerative diseases like ALS, I am excited to see if my ‘prion view’ of brain disease will help us determine how ALS develops, and how we can stop it,” says Sim.