Matrin 3 in neuromuscular disease: physiology and pathophysiology

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.

Figure 1. MATR3 domain structure and functions in normal and pathological contexts.

(A) MATR3 has two zinc finger (ZF) and two RNA-recognition motif (RRM) domains, with the remainder of the protein consisting of an intrinsically disordered sequence as measured by a high Predictor of Natural Disordered Regions (PONDR) score (128). Pathogenic mutations are located across the disordered stretches of MATR3; although the majority of mutations reported to date are linked to ALS, a subset is implicated in ALS/distal myopathy (violet) or ALS/dementia (blue). (B) Although predominantly localized in the nucleus, MATR3 is tied to several nucleic acid–related processes in both nuclear and cytoplasmic compartments. Three distinct but not mutually exclusive patterns of MATR3 pathology are observed in neuromuscular disease: nuclear enrichment, cytoplasmic redistribution, and cytoplasmic aggregation. Nuclear overabundance is predicted to drive chromatin, transcriptional, and splicing aberrations. In addition, MATR3 redistribution and aggregation in the cytoplasm — representing cytosolic gain and loss of function, respectively — may disrupt RNA stability and transport.