Interaction of myocilin with gamma-synuclein affects its secretion and aggregation.
Mutations in the gene encoding human myocilin are associated with some cases of juvenile and early-onset glaucoma. Glaucomatous mutations prevent myocilin from being secreted. The analysis of the defects associated with mutations point to the existence of factor(s) in addition to mutations that might be implicated in the development of glaucoma. In the present paper, we found that interaction of myocilin with one of the members of the synuclein family alters its properties, including its ability to be secreted. Results of immunoprecipitation show that myocilin is a gamma-synuclein-interacting protein. Further analysis demonstrated that both myocilin and gamma-synuclein are expressed in human TM cells, immortalized rat ganglion (RGC-5) cells, and HT22 hippocampal neurons. According to Western blotting, in addition to monomeric form with molecular weight 17 kDa gamma-synuclein is present as higher molecular weight forms ( approximately 35 and 68 KDa), presumably dimer and tetramer. Myocilin and gamma-synuclein have partially overlapping perinuclear localization. Dexamethasone upregulates myocilin expression in RGC-5 cells and HT22 hippocampal neurons. We found alterations of myocilin properties as a result of its interaction with gamma-synuclein. In cultured cells, gamma-synuclein upregulates myocilin expression, inhibits its secretion and prevents the formation of high molecular weight forms of myocilin. Although both alpha-synuclein and gamma-synuclein are expressed in HTM cells, only gamma-synuclein interacts with myocilin and alters its properties. We conclude that myocilin and gamma-synuclein interact and as a result, myocilin's properties are changed. Since myocilin and gamma-synuclein have partially overlapping intracellular localization in cell types that are implicated in glaucoma development, their interaction may play an important role in glaucoma.
Surgucheva
Irina
I
Retinal Disease Research Laboratory, Veterans Administration Medical Center, 4801 Linwood Blvd, Kansas City, MO 66148, USA.
Park
Bum-Chan
BC
Yue
Beatrice Y J T
BY
Tomarev
Stanislav
S
Surguchov
Andrei
A
D000293:Adolescent; D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism; D051845:gamma-Synuclein / Q000235:genetics / Q000378:metabolism*; D000099179:Myocilin
D000893:Anti-Inflammatory Agents; D003598:Cytoskeletal Proteins; D003907:Dexamethasone; D005136:Eye Proteins; D006023:Glycoproteins; D051844:alpha-Synuclein; D051845:gamma-Synuclein; D000099179:Myocilin