Aberrant Cleavage of TDP-43 Enhances Aggregation and Cellular Toxicity

Authors

Young-Jie Zhang, Mayo Clinic College of Medicine
Ya-Fei Xu, Mayo Clinic College of Medicine
Casey Cook, Mayo Clinic College of Medicine
Tania F. Gendron, Mayo Clinic College of Medicine
Paul Roettges, Mayo Clinic College of Medicine
Christopher D. Link, University of ColoradoFollow
Wen-Lang Lin, Mayo Clinic College of Medicine
Jimei Tong, Mayo Clinic College of Medicine
Monica Castanedes-Casey, Mayo Clinic College of Medicine
Peter Ash, Mayo Clinic College of Medinice
Jennifer Gass, Mayo Clinic College of Medicine
Vijayaraghavan Rangachari, University of Southern MississippiFollow
Emanuele Buratti, International Centre for Genetic Engineering and Biotechnology
Francisco Baralle, International Centre for Genetic Engineering and Biotechnology
Todd E. Golde, Mayo Clinic College of Medicine
Dennis W. Dickson, Mayo Clinic College of Medicine
Leonard Petrucelli, Mayo Clinic College of MedicineFollow

Document Type

Article

Publication Date

5-5-2009

Department

Chemistry and Biochemistry

School

Mathematics and Natural Sciences

Abstract

Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining histopathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a approximately 25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

106

Issue

18

First Page

7607

Last Page

7612

Recommended Citation

Zhang, Y., Xu, Y., Cook, C., Gendron, T. F., Roettges, P., Link, C. D., Lin, W., Tong, J., Castanedes-Casey, M., Ash, P., Gass, J., Rangachari, V., Buratti, E., Baralle, F., Golde, T. E., Dickson, D. W., Petrucelli, L. (2009). Aberrant Cleavage of TDP-43 Enhances Aggregation and Cellular Toxicity. Proceedings of the National Academy of Sciences of the United States of America, 106(18), 7607-7612.
Available at: https://aquila.usm.edu/fac_pubs/7534