UMMS Affiliation

Department of Neurology; Graduate School of Biomedical Sciences

Publication Date

2019-05-15

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Molecular Biology | Nervous System Diseases | Neuroscience and Neurobiology | Nucleic Acids, Nucleotides, and Nucleosides

Abstract

Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease-linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function, and disease have not been explored. Here, using primary cortical and motor neurons, we found that excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by excitotoxicity included TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS). We noted that FUS is translocated through a calcium-dependent mechanism and that its translocation coincides with striking alterations in nucleocytoplasmic transport. Further, glutamate-induced up-regulation of glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) in neurons depended on FUS expression, consistent with a functional role for FUS in excitotoxic stress. These findings reveal molecular links among prominent factors in neurodegenerative diseases, namely excitotoxicity, disease-associated RBPs, and nucleocytoplasmic transport.

Keywords

RNA transport, amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease), excitatory neurotransmission, excitotoxicity, fused in sarcoma/translocated in liposarcoma (FUS/TLS), glutamate, glutamate ionotropic receptor AMPA type subunit 2 (Gria2), glutamate receptor 2 (GluA2), neurodegeneration, nucleocytoplasmic transport

Rights and Permissions

© 2019 by The American Society for Biochemistry and Molecular Biology, Inc. Publisher PDF posted after 12 months as allowed by the publisher's author rights policy at http://www.jbc.org/site/misc/edpolicy.xhtml#copyright.

DOI of Published Version

10.1074/jbc.RA118.005933

Source

J Biol Chem. 2019 May 15. pii: jbc.RA118.005933. doi: 10.1074/jbc.RA118.005933. [Epub ahead of print] Link to article on publisher's site

Journal/Book/Conference Title

The Journal of biological chemistry

Related Resources

Link to Article in PubMed

PubMed ID

31092554

Available for download on Friday, May 15, 2020

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