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. 2005 Sep;25(6):1009–1033. doi: 10.1007/s10571-005-8471-4

Interaction of Myocilin with γ-Synuclein Affects Its Secretion and Aggregation

Irina Surgucheva 1,4, Bum-Chan Park 2, Beatrice Y J T Yue 2, Stanislav Tomarev 3, Andrei Surguchov 1,4,✉
PMCID: PMC11529489  PMID: 16392033

Abstract

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 γ-synuclein-interacting protein. Further analysis demonstrated that both myocilin and γ-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 γ-synuclein is present as higher molecular weight forms (∼35 and 68 KDa), presumably dimer and tetramer. Myocilin and γ-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 γ-synuclein. In cultured cells, γ-synuclein upregulates myocilin expression, inhibits its secretion and prevents the formation of high molecular weight forms of myocilin. Although both α-synuclein and γ-synuclein are expressed in HTM cells, only γ-synuclein interacts with myocilin and alters its properties.

We conclude that myocilin and γ-synuclein interact and as a result, myocilin's properties are changed. Since myocilin and γ-synuclein have partially overlapping intracellular localization in cell types that are implicated in glaucoma development, their interaction may play an important role in glaucoma.

Key Words: myocilin, synuclein, glaucoma, ganglion cells

Abbreviations used:

AA

amino acids

CNS

central nervous system

co-IP

co-immunoprecipitation

DMEM

Dulbecco's modified Eagle's medium

FBS

fetal bovine serum

HTM

human trabecular meshwork

ICC

immunocytochemistry

IOP

intraocular pressure

IP

immunoprecipitation

ONH

optic nerve head

PA

paraformaldehyde

PBS

phosphate buffered saline

PCR

polymerase chain reaction

PD

Parkinson's disease

POAG

primary open-angle glaucoma

RGC

retinal ganglion cells

RT

room temperature

SDS–PAGE

sodium dodecyl sulfate–polyacrylamide gel electrophoresis

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