Chasing down the PPIA pathway: Protecting where the brain and muscles connect in ALS

In healthy cells, peptidyl-prolyl isomerase A (PPIA) is a chaperone protein, meaning it helps ensure that other proteins function correctly within the body. Previous research conduced in ALS mouse models has shown that PPIA is produced in high levels in the central nervous system (the brain and spinal cord), leading researchers to investigate what role it might play in the disease. It is speculated that the protein may contribute to ALS by binding to a receptor in the cell called EMMPRIN, which triggers the release of inflammatory molecules and an enzyme called matrix metalloproteinase 9 (MMP-9). In animal models of ALS, higher levels of MMP-9 have been associated to an increased degeneration of motor neurons, which are the cells in the brain responsible for controlling voluntary movements.

New research speculates that the activation of the PPIA/EMMPRIN/MMP-9 pathway contributes to a “dying-back” mechanism, which is a theory that cell damage in ALS starts at the muscle and/or at the connection point between a motor neuron and muscle, called the neuromuscular junction (NMJ). Damage to the NMJ then contributes to degeneration of motor neurons and the loss of communication between the brain and muscles.

In this research project, Marion aims to further understand the role of the PPIA/EMMPRIN/MMP-9 pathway and asses its potential as a therapeutic target. She will look at how this pathway acts in muscle and at the NMJ during ALS progression, as well as creating a new 3D cell culture to study the pathway. Finally, she will test the efficacy of an anti-EMMPRIN antibody in a mouse model of the disease to assess if blocking this pathway can protect motor neurons in ALS. Marion’s research aims to not only add to a greater understanding of ALS, but it may also lead to new therapeutic possibilities for the disease.

Through the ALS Canada Research Program, Dr. Silvia Pozzi, Marion’s supervisor, was a recipient of the 2020 ALS Canada-Brain Canada Career Transition Award, with the research project titled ” Extracellular PPIA: a new target for an antibody-based therapeutic approach for ALS.” This award supported Dr. Pozzi in becoming an established researcher in her field, mentoring the next generation of promising early career researchers working in ALS.