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Originally published online as doi:10.2353/ajpath.2010.090194 on December 3, 2009

Published online before print December 3, 2009
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(American Journal of Pathology. 2010;176:343-352.)
© 2010 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2010.090194

Differential Effects of Myocilin and Optineurin, Two Glaucoma Genes, on Neurite Outgrowth

Takahisa Koga, Xiang Shen, Jeong-Seok Park, Ye Qiu, Bum-Chan Park, Rajalekshmy Shyam and Beatrice Y.J.T. Yue

From the Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, College of Medicine, Chicago, Illinois

Myocilin and optineurin are two genes linked to glaucoma, a major blinding disease characterized by progressive loss of retinal ganglion cells (RGCs) and their axons. To investigate the effects of force-expressed wild-type and mutant myocilin and optineurin on neurite outgrowth in neuronal cells, we transiently transfected cells with pEGFP-N1 (mock control) as well as myocilin and optineurin plasmids including pMYOCWT-EGFP, pMYOCP370L-EGFP, pMYOC1-367-EGFP, pOPTNWT-EGFP, and pOPTNE50K-EGFP. PC12 cells transfected with pEGFP-N1 produced, as anticipated, long and extensive neuritis on nerve growth factor induction. The neurite length in those cells transfected with myocilin constructs was shortened and the number of neurites was also reduced. A similar inhibitory effect on neurite outgrowth was also elicited by myocilin transfection in RGC5 cells. In contrast, neither transfection of the optineurin constructs pOPTNWT-EGFP and pOPTNE50K-EGFP nor the myocilin and optineurin small-interfering RNA treatments induced significant alterations in neurite outgrowth. Transfection with the wild-type optineurin construct, but not with that of the wild-type myocilin, increased the apoptotic activity in cells. These results demonstrated that the two glaucoma genes, myocilin and optineurin, exhibited differential effects on neurite outgrowth. They may contribute to the development of neurodegenerative glaucoma via distinct mechanisms.






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