Abstract
Mutations in Matrin 3 have recently been linked to ALS, though the mechanism that induces disease in these patients is unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry using NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin 3 in mRNA transport centered on proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co-localization with endogenous Matrin 3 and increased co-localization with specific TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and more specifically the mRNA of TDP-43 and FUS. Our findings identify a potential pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS.
Highlights
Exome sequencing was used to identify four mutations in the RNA-binding protein Matrin 3 attributed to familial ALS: S85C, F115C, P154S and T622A10
A recent study demonstrated that mutant Matrin 3 protein remains predominately in the nucleus when transiently overexpressed in multiple cell types[25]
We focused on the mRNA of TDP-4310 and FUS30, two RNA-binding proteins previously linked to ALS, both of which have been shown to bind to Matrin 3
Summary
Exome sequencing was used to identify four mutations in the RNA-binding protein Matrin 3 attributed to familial ALS: S85C, F115C, P154S and T622A10. Others have shown that expression of ALS linked mutations in Matrin 3 in a cell culture model does not result in gross mislocalization of the www.nature.com/scientificreports/. Due to the diverse roles of Matrin 3, we sought to identify functional alterations caused by ALS-linked mutations. We further demonstrate altered global mRNA nuclear export in cells expressing mutant Matrin 3 protein. Our results identify proteins that interact with wildtype and each mutant Matrin 3 protein, as well as a novel function of Matrin 3 in regulating mRNA nuclear export. These findings support a critical role for RNA processing and transport in the pathogenesis of ALS
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