Matrin3: Disorder and ALS Pathogenesis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons in the brain and spinal cord. ALS is associated with protein misfolding and inclusion formation involving RNA-binding proteins, including TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS). The 125-kDa Matrin3 is a highly conserved nuclear DNA/RNA-binding protein that is implicated in many cellular processes, including binding and stabilizing mRNA, regulating mRNA nuclear export, modulating alternative splicing, and managing chromosomal distribution. Mutations in MATR3, the gene encoding Matrin3, have been identified as causal in familial ALS (fALS). Matrin3 lacks a prion-like domain that characterizes many other ALS-associated RNA-binding proteins, including TDP-43 and FUS, however, our bioinformatics analyses and preliminary studies document that Matrin3 contains long intrinsically disordered regions that may facilitate promiscuous interactions with many proteins and may contribute to its misfolding. In addition, these disordered regions in Matrin3 undergo numerous post-translational modifications, including phosphorylation, ubiquitination and acetylation that modulate the function and misfolding of the protein. Here we discuss the disordered nature of Matrin3 and review the factors that may promote its misfolding and aggregation, two elements that might explain its role in ALS pathogenesis.

Genome-wide landscape of RNA-binding protein (RBP) networks as potential molecular regulators of psychiatric co-morbidities: a computational analysis

“…The target transcripts of PCBP1 were reported to be associated with neuropathies [77], while PCBP2 was found to be downregulated in ALS [78]. Matrin3 is an established RBP associated with ALS [79], which was also detected to be a hub RBP in the network. Thus, the hub proteins identified in the RBP network in this study are known to be involved in a number of neurological conditions, which suggests a shared molecular basis underlying these disorders.…”

MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy

“…Since MATR3 is a protein involved in many biological processes, 43 , 50 administration of full-length MATR3 could lead to side effects. Indeed, previous reports showed toxicity associated with full-length MATR3 overexpression.…”

MicroRNA biomarkers as next-generation diagnostic tools for neurodegenerative diseases: a comprehensive review

“…In ALS, miRNAs play a crucial role in phase transition by promoting or inhibiting the formation of multivalent contacts between phase-separating macromolecules and associating with or excluding other proteins and nucleic acids. These processes can promote or mitigate the proteinopathies that underlie neurodegeneration in ALS (Salem et al, 2022). For example, the PTM of the SOD1 protein, involved in familial cases of ALS, can contribute to disease progression.…”

“…Frontiers in Molecular Neuroscience 18 frontiersin.org development of practical diagnostic tools (Salem et al, 2022). Table 9 lists miRNAs involved in ALS pathogenesis.…”