ALS Associated Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export

ABSTRACT: Mutations in Matrin 3 have recently been linked to ALS, though the mechanism of disease in these patients is still unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry experiments in NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin in mRNA transport centered around 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 TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and the mRNA of ALS linked proteins TDP-43 and FUS. Our findings demonstrate the first pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Amyotrophic Lateral Sclerosis Type 21

SUBMITTER: Krystine Mansfield  

LAB HEAD: Patrick Pirrotte

PROVIDER: PXD007710 | Pride | 2017-11-15

REPOSITORIES: Pride