Proteomics reveal Cochlin deposits associated with glaucomatous trabecular meshwork.
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.
Bhattacharya
Sanjoy K
SK
Cole Eye Institute and Lerner Research Institute (i31), Cleveland Clinic Foundation, Cleveland, OH 44195, USA. bhattas@ccf.org
Rockwood
Edward J
EJ
Smith
Scott D
SD
Bonilha
Vera L
VL
Crabb
John S
JS
Kuchtey
Rachel W
RW
Robertson
Nahid G
NG
Peachey
Neal S
NS
Morton
Cynthia C
CC
Crabb
John W
JW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D016022:Case-Control Studies; D002449:Cell Aggregation; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins; D018507:Gene Expression Regulation, Developmental; D005901:Glaucoma / Q000378:metabolism* / Q000473:pathology*; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D011506:Proteins / Q000378:metabolism*; D040901:Proteomics; D014129:Trabecular Meshwork / Q000378:metabolism* / Q000473:pathology*
C110668:COCH protein, human; C491729:Coch protein, mouse; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D011506:Proteins; D003094:Collagen