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J. Biol. Chem., Vol. 283, Issue 19, 13302-13309, May 9, 2008

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Disturbance of Nuclear and Cytoplasmic TAR DNA-binding Protein (TDP-43) Induces Disease-like Redistribution, Sequestration, and Aggregate Formation^*

Matthew J. Winton, Lionel M. Igaz, Margaret M. Wong, Linda K. Kwong, John Q. Trojanowski, and Virginia M.-Y. Lee¹

From the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and the Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

TAR DNA-binding protein 43 (TDP-43) is the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Although normal TDP-43 is a nuclear protein, pathological TDP-43 is redistributed and sequestered as insoluble aggregates in neuronal nuclei, perikarya, and neurites. Here we recapitulate these pathological phenotypes in cultured cells by altering endogenous TDP-43 nuclear trafficking and by expressing mutants with defective nuclear localization (TDP-43-NLS) or nuclear export signals (TDP-43-NES). Restricting endogenous cytoplasmic TDP-43 from entering the nucleus or preventing its exit out of the nucleus resulted in TDP-43 aggregate formation. TDP-43-NLS accumulates as insoluble cytoplasmic aggregates and sequesters endogenous TDP-43, thereby depleting normal nuclear TDP-43, whereas TDP-43-NES forms insoluble nuclear aggregates with endogenous TDP-43. Mutant forms of TDP-43 also replicate the biochemical profile of pathological TDP-43 in FTLD-U/ALS. Thus, FTLD-U/ALS pathogenesis may be linked mechanistically to deleterious perturbations of nuclear trafficking and solubility of TDP-43.

Received for publication, January 14, 2008 , and in revised form, February 27, 2008.

^* This work was supportred, in whole or in part, by National Institutes of Health Grants AG17586 and AG10124. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Maloney Bldg. 3rd Floor, HUP, 3600 Spruce St., Philadelphia, PA 19104-4283. E-mail: vmylee{at}mail.med.upenn.edu.

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