Published online before print March 16, 2004, 10.1073/pnas.0305755101
April 20, 2004 | vol. 101 | no. 16 | 6226-6230
Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury
A. W. Harrington * , B. Leiner , C. Blechschmitt , J. C. Arevalo ¶, R. Lee ||, K. Mörl **, M. Meyer , B. L. Hempstead ||, S. O. Yoon * and K. M. Giehl ¶¶
*Department of Cellular and Molecular Biochemistry, Center for Molecular Neurobiology, and Biochemistry Program, Ohio State University, Columbus, OH 43210; Department of Anatomy, University of Saarland, 66421 Homburg, Germany; ¶Skirball Institute of Biomedical Medicine, New York University Medical School, New York, NY 10016; ||Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10016; **Institute of Biochemistry, University of Leipzig, D-04109 Leipzig, Germany; and Institute of Ophthalmology, University College London, London WC1N 2AP, United Kingdom
Edited by Hans Thoenen, Max Planck Institute of Neurobiology, Martinsried, Germany and approved February 2, 2004 (received for review September 8, 2003)
The unprocessed precursor of the neurotrophin nerve growth factor (NGF), proNGF, has been suggested to be a death-inducing ligand for the neurotrophin receptor p75. Whether proNGF is a true pathophysiological ligand that is secreted, binds p75, and activates cell death in vivo, however, has remained unknown. Here, we report that after brain injury, proNGF was induced and secreted in an active form capable of triggering apoptosis in culture. We further demonstrate that proNGF binds p75 in vivo and that disruption of this binding results in complete rescue of injured adult corticospinal neurons. These data together suggest that proNGF binding to p75 is responsible for the death of adult corticospinal neurons after lesion, and they help to establish proNGF as the pathophysiological ligand that activates the cell-death program by means of p75 after brain injury. Interference in the binding of proNGF to p75 may provide a therapeutic approach for the treatment of disorders involving neuronal loss.
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This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: BDNF, brain-derived neurotrophic factor; CSN, corticospinal neurons; NGF, nerve growth factor; NT3, neurotrophin 3; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling; CSF, cerebrospinal fluid.
See Commentary on page 5703.
A.W.H. and B.L. contributed equally to this work.
Present address: Physiologishes Institut, Ludwigs-Maximillian Universität Munich, Pettenkoferstrasse 12, 80336 Munich, Germany.
To whom correspondence may be addressed at: Department of Molecular Cellular Biochemistry, Center for Molecular Neurobiology, Ohio State University, 1060 Carmack Road, Columbus, OH 43210. E-mail: yoon.84@osu.edu. ¶¶To whom correspondence may be sent at the present address: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9039. E-mail: klaus.giehl@utsouthwestern.edu. |
