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Abstract #46667 Published in IGR 13-3
Role of glutamate transporters in glaucoma
Yanagisawa M; Kato S; Takeda T; Aida T; Harada T; Fuse N; Tanaka KNeuroscience Research 2011; 71: e200
Glaucoma is one of the leading causes of bilateral blindness. Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs) and is often associated with elevated intraocular pressure (IOP). However, patients with normal tension glaucoma (NTG), a subtype of primary open angle glaucoma (POAG), develop the disease without IOP elevation. The molecular pathways leading to the pathology of NTG and POAG are still unclear. Elucidating IOP-independent factors, such as excitotoxicity, would be necessary to understand the pathogenesis of glaucoma. Glutamate transporter is the only mechanism for the clearance of glutamate in retina. In the inner plexiform layer where synapses on RGCs exist, there are 3 glutamate transporters: GLT-1, EAAC1, and GLAST. We have recently observed that GLASTand EAAC1-knockout mice show spontaneously occurring RGC loss and typical glaucomatous damage of the optic nerve without elevated IOP. These observations suggest GLAST and EAAC1 as candidate genes in glaucoma. In the present study, we performed mutation analysis of the human GLAST and EAAC1 gene in Japanese glaucoma patients.Weidentified 2 novel GLAST missense mutations from three glaucoma patients. To examine the functional significance of these mutations, radioactive glutamate uptake assays were performed in HEK 293T cells. One of these two mutations showed a reduction of glutamate uptake with the reduced surface expression of GLAST. Furthermore, arundic acid, a glial glutamate transporter potentiator, can rescue RGC death in GLAST heterozygous mice. Our findings indicate that the mutation of GLAST is associated with human glaucoma and enhancing the function of GLAST may be useful for the treatment of glaucoma.
M. Yanagisawa. Dev. of Mol Neurosci., Grad. Sch. of Biomedi. Sci. Tokyo Medi. and Dent. Unive., Tokyo, Japan.
Classification:
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
3.6 Cellular biology (Part of: 3 Laboratory methods)
