title: Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death.
abstract: Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFα triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma.
authors.affiliation: Department of Ophthalmology, The Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Gregory
authors.forename: Caroline G
authors.initials: CG
authors.lastname: Hackett
authors.forename: Emma F
authors.initials: EF
authors.lastname: Abernathy
authors.forename: Karen S
authors.initials: KS
authors.lastname: Lee
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Saff
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Hohlbaum
authors.forename: Krishna-Sulayman L
authors.initials: KS
authors.lastname: Moody
authors.forename: Maura W
authors.initials: MW
authors.lastname: Hobson
authors.forename: Alexander
authors.initials: A
authors.lastname: Jones
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Kolovou
authors.forename: Saoussen
authors.initials: S
authors.lastname: Karray
authors.forename: Andrea
authors.initials: A
authors.lastname: Giani
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
authors.forename: Dong Feng
authors.initials: DF
authors.lastname: Chen
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Ksander
mesh_terms: D000818:Animals; D016923:Cell Death; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism* / Q000494:pharmacology; D005901:Glaucoma / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D007267:Injections; D051379:Mice; D008817:Mice, Mutant Strains; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D012162:Retinal Degeneration / Q000150:complications / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor