Abstract
Abnormalities in nucleic acid processing are associated with the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in Matrin 3 (MATR3), a poorly understood DNA- and RNA-binding protein, cause familial ALS/FTD, and MATR3 pathology is a feature of sporadic disease, suggesting that MATR3 dysfunction is integrally linked to ALS pathogenesis. Using a rat primary neuron model to assess MATR3-mediated toxicity, we noted that neurons were bidirectionally vulnerable to MATR3 levels, with pathogenic MATR3 mutants displaying enhanced toxicity. MATR3's zinc finger domains partially modulated toxicity, but elimination of its RNA recognition motifs had no effect on survival, instead facilitating its self-assembly into liquid-like droplets. In contrast to other RNA-binding proteins associated with ALS, cytoplasmic MATR3 redistribution mitigated neurodegeneration, suggesting that nuclear MATR3 mediates toxicity. Our findings offer a foundation for understanding MATR3-related neurodegeneration and how nucleic acid binding functions, localization, and pathogenic mutations drive sporadic and familial disease.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder resulting in the death of upper and lower motor neurons (Charcot and Joffroy, 1869)
We first asked how Matrin 3 (MATR3) expression is related to neurodegeneration using longitudinal fluorescence microscopy (LFM), a sensitive high-content imaging system that we assembled for assessing neuronal function and survival at the single-cell level
Cultures were imaged by fluorescence microscopy at 24 hr intervals for 10 days, and custom scripts used to generate uniquely labeled regions of interest (ROIs) corresponding to each cell (Figure 1B)
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder resulting in the death of upper and lower motor neurons (Charcot and Joffroy, 1869). A more recent report reclassified a subset of patients with this diagnosis as having ALS and noted several additional MATR3 mutations in individuals with ALS and frontotemporal dementia (FTD), placing MATR3 in a family of genes implicated in familial ALS, FTD, and myopathy This family includes TIA1, VCP, p62/ SQSTM1, hnRNPA1, and hnRNPA2/B1, mutations in which lead to multisystem proteinopathy characterized by variable involvement of muscle and bone in addition to the central nervous system (Hocking et al, 2002; Fecto et al, 2011; Kimonis et al, 2008; Johnson et al, 2010; Kim et al, 2013; Klar et al, 2013; Johnson et al, 2014; Mackenzie et al, 2017). We examine how disease-associated MATR3 mutations affect these properties to enhance neurodegeneration
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