Damage-induced neuronal endopeptidase (DINE) is a unique metallopeptidase expressed in response to neuronal damage and activates superoxide scavengers

Damage-induced neuronal endopeptidase (DINE) is a unique metallopeptidase expressed in response to neuronal damage and activates superoxide scavengers

Departments of ^*Anatomy, ^†Oral and Maxillofacial Surgery, ^‡Anesthesiology and Critical Care Medicine, and ^§Orthopedic Surgery, Asahikawa Medical College, 2–1-1–1 Midorigaoka-Higashi, Asahikawa 078-8510, Japan; and ^¶Department of Degenerative Neurological Diseases, National Institute of Neuroscience, Kodaira, Tokyo 187-8502, Japan

Edited by Eugene Roberts, Beckman Research Institute of the City of Hope, Duarte, CA, and approved February 7, 2000 (received for review November 22, 1999)

Abstract

We isolated a membrane-bound metallopeptidase, DINE (damage-induced neuronal endopeptidase), by differential display PCR using rat normal and axotomized hypoglossal nuclei. The most marked properties of DINE were neuron-specific expression and a striking response to axonal injury in both the central nervous system and peripheral nervous system. For instance, cranial and spinal nerve transection, ischemia, corpus callosum transection, and colchicine treatment increased DINE mRNA expression in the injured neurons, whereas kainate-induced hyperexcitation, immobilization, and osmotic stress failed to up-regulate DINE mRNA. Expression of DINE in COS cells partially inhibited C2-ceramide-induced apoptosis, probably because of the activation of antioxidant enzymes such as Cu/Zn-superoxide dismutase, Mn-superoxide dismutase, and glutathione peroxidase through the proteolytic activity of DINE. These data provide insight into the mechanism of how injured neurons protect themselves against neuronal death.

Footnotes

↵ ‖ To whom reprint requests should be addressed. E-mail: kiyama{at}asahikwa-med.ac.jp.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AB023896, AB026293, and AB026294).
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.070509897.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.070509897
Abbreviations:

DINE,

damage-induced neuronal endopeptidase;

DD-PCR,

differential display PCR;

PC,

proprotein convertase;

ECE,

endothelin converting enzyme;

CNS,

central nervous system;

MCA,

middle cerebral artery;

RACE,

rapid amplification of cDNA ends;

SOD,

superoxide dismutase;

GPX,

glutathione peroxidase;

NEP,

neutral endopeptidase