Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the loss of upper and lower motor neurons, leading to paralysis and death. Despite decades of research, there are still no disease-altering therapies for patients with ALS. Accumulating evidence implicates RNA-binding protein (RBP) dysfunction as a key feature in the pathogenesis of ALS and related disorders such as frontotemporal dementia (FTD). Notably, the vast majority (>95%) of individuals with ALS display cytoplasmic mislocalization and aggregation of the RBP TDP-43 (transactive response element DNA/RNA-binding protein, 43 kDa) in affected tissue. In addition, mutations in the genes encoding TDP-43 and other RBPs cause disease. Several of these RBPs, including the nuclear matrix protein Matrin 3 (MATR3), are implicated not only in combined ALS/FTD, but also myopathy. MATR3 mutations are responsible for familial ALS, FTD, and myopathy, and post-mortem studies demonstrated MATR3 aggregation and mislocalization in sporadic disease patients who lack any identifiable mutations, suggesting that MATR3 dysregulation may have a conserved pathogenic role in both sporadic and familial disease. Despite this, little is known about MATR3 function, how it might be disrupted in disease, and the effects of pathogenic mutations on MATR3 behavior. This proposal seeks to expand our understanding of MATR3 and its contribution to disease. I previously established a neuronal model of MATR3-mediated neurodegeneration and used this model to highlight the importance of MATR3 nucleic acid binding and nucleocytoplasmic localization in disease. I also identified a subset of pathogenic MATR3 mutations that affect protein solubility and dynamics. Here, I will build upon this work by testing the hypothesis that disease-associated MATR3 mutations result in neurodegeneration by impacting MATR3 turnover and its DNA/RNA-binding properties. These studies may reveal new mechanisms underlying MATR3-mediated toxicity in ALS and related disorders, with broad relevance not only for rare familial disease due to MATR3 mutations but also for sporadic disease. Additionally, it will offer me the opportunity to develop essential skills in hypothesis testing, experimental design, data analysis, and scientific communication that will be critical for success in my intended career as a physician-scientist in the field of neurological disease.
A growing body of evidence implicates RNA-binding proteins as important pathogenic mediators in amyotrophic lateral sclerosis and related disorders. Matrin 3 (MATR3) is a DNA- and RNA-binding protein that causes familial disease when mutated and exhibits pathology in sporadic disease, pointing to a potentially conserved role in neurodegeneration. In this proposal, I will explore the mechanisms regulating MATR3 turnover and nucleic acid binding, as well as the impact of pathogenic MATR3 mutations on these pathways.
