Enhancedoptineurin E50k-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma

Yuriko Minegishi, Daisuke Iejima, Hiroaki Kobayashi, Zai Long Chi, Kazuhide Kawase, Tetsuya Yamamoto, Tomohisa Seki, Shinsuke Yuasa, Keiichi Fukuda, Takeshi Iwata

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104 Citations (Scopus)


Glaucoma is the leading cause for blindness affecting 60 million people worldwide. The optineurin (OPTN) E50K mutation was first identified in familial primary open-angle glaucoma (POAG), the onset of which is not associated with intraocular pressure (IOP) elevation, and is classified as normal-tension glaucoma (NTG). Optineurin (OPTN) is a multifunctional protein and its mutations are associated with neurodegenerative diseases such as POAG and amyotrophic lateral sclerosis (ALS). We have previously described an E50K mutation- carrying transgenic (E50K-tg) mouse that exhibited glaucomatous phenotypes of decreased retinal ganglion cells (RGCs) and surrounding cell death at normal IOP. Further phenotypic analysis of these mice revealed persistent reactive gliosis and E50K mutant protein deposits in the outer plexiform layer (OPL). Over-expression of E50K in HEK293 cells indicated accumulation of insoluble OPTN in the endoplasmic reticulum (ER). This phenomenon was consistent with the results seen in neurons derived from induced pluripotent stem cells (iPSCs) from E50K mutation-carrying NTG patients. The E50K mutant strongly interacted with TANKbinding kinase 1 (TBK1), which prohibited the proper oligomerization and solubility of OPTN, both of which are important for OPTN intracellular transition. Treatment with a TBK1 inhibitor, BX795, abrogated the aberrant insolubility of the E50K mutant. Here, we delineated the intracellular dynamics of the endogenous E50K mutant protein for the first time and demonstrated how this mutation causes OPTN insolubility, in association with TBK1, to evoke POAG.

Original languageEnglish
Article numberddt210
Pages (from-to)3559-3567
Number of pages9
JournalHuman molecular genetics
Issue number17
Publication statusPublished - 2013 Sept

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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