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J. Biol. Chem., Vol. 283, Issue 43, 29156-29165, October 24, 2008

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2-Macroglobulin Is a Mediator of Retinal Ganglion Cell Death in Glaucoma^*

ZhiHua Shi¹, Marcelo Rudzinski¹, Karen Meerovitch^¶1, Frédéric Lebrun-Julien^||, Elena Birman, Adriana Di Polo^||**, and H. Uri Saragovi²

From the Lady Davis Institute-Jewish General Hospital, Departments of Pharmacology and Therapeutics, ^¶Biochemistry, and Oncology, and the Cancer Center, McGill University, Montreal, Canada and the Departments of ^||Pathology and Cell Biology and ^**Ophthalmology, Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montreal, Quebec H3T 1J4, Canada

Glaucoma is defined as a chronic and progressive optic nerve neuropathy, characterized by apoptosis of retinal ganglion cells (RGC) that leads to irreversible blindness. Ocular hypertension is a major risk factor, but in glaucoma RGC death can persist after ocular hypertension is normalized. To understand the mechanism underlying chronic RGC death we identified and characterized a gene product, 2-macroglobulin (2M), whose expression is up-regulated early in ocular hypertension and remains up-regulated long after ocular hypertension is normalized. In ocular hypertension retinal glia up-regulate 2M, which binds to low-density lipoprotein receptor-related protein-1 receptors in RGCs, and is neurotoxic in a paracrine fashion. Neutralization of 2M delayed RGC loss during ocular hypertension; whereas delivery of 2M to normal eyes caused progressive apoptosis of RGC mimicking glaucoma without ocular hypertension. This work adds to our understanding of the pathology and molecular mechanisms of glaucoma, and illustrates emerging paradigms for studying chronic neurodegeneration in glaucoma and perhaps other disorders.

Received for publication, March 26, 2008 , and in revised form, June 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA82642. This work was also supported by Canadian Institutes of Health Research Grants MT13265 and MOP57690. Patents have been licensed to Mimetogen Pharmaceuticals Inc., and H. U. S. discloses interest in the company. 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.

¹ These authors contributed equally.

² To whom correspondence should be addressed: 3755 Cote St. Catherine, E-535, Montreal, Quebec H3T 1E2, Canada. E-mail: uri.saragovi{at}mcgill.ca.

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