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J. Biol. Chem., Vol. 280, Issue 7, 6080-6084, February 18, 2005

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Proteomics Reveal Cochlin Deposits Associated with Glaucomatous Trabecular Meshwork^*

Sanjoy K. Bhattacharya, Edward J. Rockwood, Scott D. Smith, Vera L. Bonilha, John S. Crabb, Rachel W. Kuchtey, Nahid G. Robertson¶, Neal S. Peachey||, Cynthia C. Morton¶, and John W. Crabb**

From the Cole Eye Institute and ^**Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, ^¶Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and ^||Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio 44106

The etiology of primary open angle glaucoma, a leading cause of age-related blindness, remains poorly defined, although elevated intraocular pressure (IOP) contributes to the disease progression. To better understand the mechanisms causing elevated IOP from aqueous humor circulation, we pursued proteomic analyses of trabecular meshwork (TM) from glaucoma and age-matched control donors. These analyses demonstrated that Cochlin, a protein associated with deafness disorder DFNA9, is present in glaucomatous but absent in normal TM. Cochlin was also detected in TM from the glaucomatous DBA/2J mouse preceding elevated IOP but found to be absent in three other mouse lines that do not develop elevated IOP. Histochemical analyses revealed co-deposits of Cochlin and mucopolysaccharide in human TM around Schlemm's canal, similar to that observed in the cochlea in DFNA9 deafness. Purified Cochlin was found to aggregate after sheer stress and to induce the aggregation of TM cells in vitro. Age-dependent in vivo increases in Cochlin were observed in glaucomatous TM, concomitant with a decrease in type II collagen, suggesting that Cochlin may disrupt the TM architecture and render components like collagen more susceptible to degradation and collapse. Overall, these observations suggest that Cochlin contributes to elevated IOP in primary open angle glaucoma through altered interactions within the TM extracellular matrix, resulting in cell aggregation, mucopolysaccharide deposition, and significant obstruction of the aqueous humor circulation.

Received for publication, September 30, 2004 , and in revised form, November 23, 2004.

^* This work was supported by the National Glaucoma Research Program of American Health Assistance Foundation (to S. K. B.), National Institutes of Health Grants DC03402 (to C. C. M.) and EY6603, EY14239, and EY015638 (to J. W. C.), a Merit Award from the Department of Veterans Affairs (to N. S. P.), a Research Center Grant from The Foundation Fighting Blindness (to J. W. C.), and funds from the Cleveland Clinic Foundation (to J. W. C.). 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 Table I and Figs. 1 and 2.

To whom correspondence should be addressed: Cole Eye Institute (i31), Cleveland Clinic Foundation, Cleveland, OH 44195. Tel.: 216-445-0676; Fax: 216-445-3670; E-mail: bhattas{at}ccf.org.

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