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In Glaucoma the Upregulated Truncated TrkC.T1 Receptor Isoform in Glia Causes Increased TNF-alpha Production, Leading to Retinal Ganglion Cell Death

  1. Author:
    Bai, Y. J.
    Shi, Z. H.
    Zhuo, Y. H.
    Liu, J.
    Malakhov, A.
    Ko, E.
    Burgess, K.
    Schaefer, H.
    Esteban, P. F.
    Tessarollo, L.
    Saragovi, H. U.

  2. Author Address

    [Bai, Yujing; Shi, ZhiHua; Saragovi, H. Uri] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Bai, Yujing; Zhuo, Yehong] Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China. [Liu, Jing; Malakhov, Andrey; Ko, Eunhwa; Burgess, Kevin] Texas A&M Univ, Dept Chem, College Stn, TX 77843 USA. [Schaefer, Henry; Esteban, Pedro F.; Tessarollo, Lino] NCI, Neural Dev Sect, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Saragovi, H. Uri] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada. [Saragovi, H. Uri] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Saragovi, H. Uri] McGill Univ, Ctr Canc, Montreal, PQ H3G 1Y6, Canada.;Saragovi, HU, McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada.;uri.saragovi@mcgill.ca
    1. Year: 2010
    2. Date: Dec
  2. Journal: Investigative Ophthalmology & Visual Science
    1. 51
    2. 12
    3. Pages: 6639-6651
  4. Type of Article: Article
  5. ISSN: 0146-0404
  1. Abstract:

    PURPOSE. Glaucoma is a distinct neuropathy characterized by the chronic and progressive death of retinal ganglion cells (RGCs). The etiology of RGC death remains unknown. Risk factors for glaucomatous RGC death are elevated intraocular pressure and glial production of tumor necrosis factor-alpha (TNF-alpha). Previously, the authors showed that glaucoma causes a rapid upregulation of a neurotrophin receptor truncated isoform lacking the kinase domain, TrkC.T1, in retina. Here they examined the biological role of TrkC.T1 during glaucoma progression. METHODS. Rat and mouse models of chronic ocular hypertension were used. Immunofluorescence Western blot analysis and in situ mRNA hybridization were used to identify cells upregulating TrkC.T1. A genetic model of engineered mice lacking TrkC.T1 (TrkC.T1(-/-)) was used to validate a role for this receptor in glaucoma. Pharmacologic studies were conducted to evaluate intravitreal delivery of agonists or antagonists of TrkC. T1, compared with controls, during glaucoma. Surviving RGCs were quantified by retrograde-labeling techniques. Production of neurotoxic TNF-alpha and alpha 2 macroglobulin were quantified. RESULTS. TrkC.T1 was upregulated in retinal glia, with a pattern similar to that of TNF-alpha. TrkC.T1(-/-) mice had normal retinas. However, during experimental glaucoma, TrkC.T1 (/) mice had lower rates of RGC death and produced less TNF-alpha than wild-type littermates. In rats with glaucoma, the pharmacologic use of TrkC antagonists delayed RGC death and reduced the production of retinal TNF-alpha. CONCLUSIONS. TrkC.T1 is implicated in glaucomatous RGC death through the control of glial TNF-alpha production. Overall, the data point to a paracrine mechanism whereby elevated intraocular pressure upregulated glial TrkC.T1 expression in glia; TrkC.T1 controlled glial TNF-alpha production, and TNF-alpha caused RGC death. (Invest Ophthalmol Vis Sci. 2010; 51: 6639-6651) DOI:10.1167/iovs.10-5431

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  2. DOI: 10.1167/iovs.10-5431
  3. View record in Web of Science®
  4. WOS: 000284837500072

Library Notes

  1. Fiscal Year: FY2010-2011
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