Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 46, Pages 28727-28734Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2012216117
Keywords
low-complexity sequence; cross-beta polymers; TDP-43; redox sensor; neurodegenerative disorders
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Funding
- National Institute of General Medical Sciences [5R35GM13130358]
- National Institute of Neurological Disorders and Stroke Grant - University of Texas Southwestern Medical Center [RO1NS115546]
- Howard Hughes Medical Institute
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A methionine-rich low complexity (LC) domain is found within a C-terminal region of the TDP43 RNA-binding protein. Self-association of this domain leads to the formation of labile cross-beta polymers and liquid-like droplets. Treatment with H2O2 caused phenomena of methi-onine oxidation and droplet melting that were reversed upon exposure of the oxidized protein to methionine sulfoxide reductase enzymes. Morphological features of the cross-beta polymers were revealed by H2O2-mediated footprinting. Equivalent TDP43 LC domain footprints were observed in polymerized hydrogels, liquid-like droplets, and living cells. The ability of H2O2 to impede cross-beta polymerization was abrogated by the prominent M337V amyotrophic lateral sclerosis-causing mutation. These observations may offer insight into the biological role of TDP43 in facilitating synapse-localized translation as well as aberrant aggregation of the protein in neurodegenerative diseases.
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