Monday, June 16, 2025
6/16/2025
Novel knock-in mouse models of ALS and myopathy-linked Matrin 3 mutations - Project Summary: The nuclear protein Matrin 3 has many roles in RNA processing including splicing and transport, and mutations in Matrin 3 gene (MATR3) have been linked to familial forms of amyotrophic lateral sclerosis (ALS) and distal myopathy with vocal cord and pharyngeal weakness (VCPDM). However, the exact role of MATR3 in ALS and myopathy is not understood. While 13 pathogenic mutations in MATR3 have been linked to ALS, the S85C mutation can induce either ALS or myopathy. Protein interactome studies have demonstrated that Matrin 3 interacts with numerous proteins involved in RNA processing. This is particularly important as RNA processing alterations have been demonstrated to be a common theme in various forms of ALS including familial forms with mutations in RNA-binding proteins such as TDP-43, FUS, and C9ORF72. Thus, studying the mechanisms of MATR3 driven pathogenesis has potential to elucidate the role of RNA binding-proteins and RNA processing in the neuron-muscular disease process. To investigate the role of MATR3 mutations in ALS and myopathy pathogenesis and disease progression we have recently generated novel knock-in mouse models that express either the S85C (ALS/VCPDM associated) or P154S (ALS associated) mutations, which we previously demonstrated led to changes in Matrin 3 protein interactions and RNA transport deficits in cultured cells. These mouse models were generated in collaboration with The Jackson Laboratory using CRISPR-Cas in order to avoid overexpression and maintain physiologic levels of Matrin 3, in contrast to most mouse models that overexpress transgenes. We hypothesize that MATR3 mutations cause RNA processing deficits which contribute to motor neuron (ALS) and muscle (myopathy) centric disease. Utilization of our novel mouse models with mutations inserted in the endogenous MATR3 gene will permit characterization of functional and molecular consequences of MATR3 mutations. Completion of this work will provide the field with two new mouse models for the study of disease mechanisms and therapeutic development.
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