Abstract
RNA-binding proteins (RBPs) are essential factors required for the physiological function of neurons, muscle, and other tissue types. In keeping with this, a growing body of genetic, clinical, and pathological evidence indicates that RBP dysfunction and/or gene mutation leads to neurodegeneration and myopathy. Here, we summarize the current understanding of matrin 3 (MATR3), a poorly understood RBP implicated not only in ALS and frontotemporal dementia but also in distal myopathy. We begin by reviewing MATR3’s functions, its regulation, and how it may be involved in both sporadic and familial neuromuscular disease. We also discuss insights gleaned from cellular and animal models of MATR3 pathogenesis, the links between MATR3 and other disease-associated RBPs, and the mechanisms underlying RBP-mediated disorders.
Highlights
ALS is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, resulting in weakness and paralysis
Mutations in the matrin 3 (MATR3)-encoding gene are responsible for neuromuscular disease, implying that this protein is critical for maintaining neurons as well as muscle, but how MATR3 mutations affect its function and/or contribute to disease pathogenesis remains unclear
Much less in known about the consequences of MATR3 DNA binding and whether the dysregulation of MATR3 chromatin targets is involved in disease
Summary
ALS is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, resulting in weakness and paralysis. ZF1 deletion promotes interaction of MATR3 with miR138-5p, and RRM removal interrupts this association [36] These data suggest that MATR3’s DNA-binding activity may antagonize its functions in RNA splicing and metabolism. Despite accumulating genetic evidence that testifies to the relationship between MATR3 mutations and human disease, the consequences and tissue specificity of the Ser85Cys mutation remain controversial This point mutation, first identified in families with VCPDM displaying myogenic and neurogenic EMG features [70, 71], was later associated with slowly progressive ALS and upper motor neuron involvement based on the presence of brisk reflexes in some patients [81]. Amyloid-β species drive MATR3 phosphorylation, but it is unknown whether this is the mechanism responsible for the MATR3 deposition noted in AD patients [93]
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