Establishing MATR3 S85C knock-in mice as a preclinical model of ALS

ALS researchers often work with mice that have been genetically modified to model ALS in humans. Yet, it can be a challenge to create mouse models with the right levels of mutated proteins to accurately represent the protein abnormalities found in people with ALS. Without the right levels, it can be difficult to tell if research findings resulted from the disease or the presence of too much protein. Previous-generation mouse models that make high levels of the mutant MATR3 protein may not accurately represent disease mechanisms.

Dr. Jeehye Park has produced a new mouse model of the MATR3 mutation using a modern gene-editing technique called CRISPR. CRISPR involves editing the mouse’s MATR3 gene directly, similar to cutting and pasting a letter in a misspelled word to correct a typo. These mice are showing ALS-like symptoms, including motor abnormalities, inflammation and misplacement of MATR3 protein from the nuclei of motor neurons into the cytoplasm, with some aggregation occurring as well. The development of these symptoms is a promising sign that these mice may be good models for studying ALS.

Dr. Park received an ALS Canada-Brain Canada Career Transition Award in 2016. This 2019 grant leverages the previous funding to provide continuing support that will allow Dr. Park to finish validating the MATR3 mice models of ALS. She hopes to publish her work so that ALS researchers around the world may use these models in future research to understand the underlying biology and mechanisms that contribute to ALS, which could help identify new treatment targets.