Abstract
Leber congenital amaurosis (LCA) is a devastating pediatric retinal degenerative disease, accounting for 20% of blindness in children attending schools for the blind. Mutations in the RPE65 gene, which encodes the retinal pigment epithelium-specific isomerohydrolase RPE65, account for 16% of all LCA cases. Recent findings have linked cone photoreceptor viability to thyroid hormone (TH) signaling. TH signaling regulates cell proliferation, differentiation, and metabolism. At the cellular level, TH action is regulated by the two iodothyronine deiodinases, DIO2 and DIO3. DIO2 converts the prohormone thyroxine (T4) to the bioactive hormone triiodothyronine (T3), and DIO3 inactivates T3 and T4. The present work investigates the effects of overexpression of DIO3 to suppress TH signaling and thereby modulate cone death/survival. Subretinal delivery of AAV5-IRBP/GNAT2-hDIO3 induced robust expression of DIO3 in the mouse retina and significantly reduced the number of TUNEL-positive cells in the cone-dominant LCA model Rpe65 −/− /Nrl −/− mice. Our work shows that suppressing TH signaling by overexpression of DIO3 preserves cones, supporting that suppressing TH signaling locally in the retina may represent a treatment strategy for LCA management.
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References
Curcio C, Baqui MM, Salvatore D, Rihn BH, Mohr S, Harney JW, Larsen PR, Bianco AC (2001) The human type 2 iodothyronine deiodinase is a selenoprotein highly expressed in a mesothelioma cell line. J Biol Chem 276:30183–30187
Dentice M, Ambrosio R, Damiano V, Sibilio A, Luongo C, Guardiola O, Yennek S, Zordan P, Minchiotti G, Colao A, Marsili A, Brunelli S, Del Vecchio L, Larsen PR, Tajbakhsh S, Salvatore D (2014) Intracellular inactivation of thyroid hormone is a survival mechanism for muscle stem cell proliferation and lineage progression. Cell Metab 20:1038–1048
Farjo R, Skaggs JS, Nagel BA, Quiambao AB, Nash ZA, Fliesler SJ, Naash MI (2006) Retention of function without normal disc morphogenesis occurs in cone but not rod photoreceptors. J Cell Biol 173:59–68
Kuiper GG, Klootwijk W, Visser TJ (2003) Substitution of cysteine for selenocysteine in the catalytic center of type III iodothyronine deiodinase reduces catalytic efficiency and alters substrate preference. Endocrinology 144:2505–2513
Kunchithapautham K, Coughlin B, Crouch RK, Rohrer B (2009) Cone outer segment morphology and cone function in the Rpe65−/− Nrl−/− mouse retina are amenable to retinoid replacement. Invest Ophthalmol Vis Sci 50:4858–4864
Ma H, Thapa A, Morris LM, Michalakis S, Biel M, Frank MB, Bebak M, Ding XQ (2013) Loss of cone cyclic nucleotide-gated channel leads to alterations in light response modulating system and cellular stress response pathways: a gene expression profiling study. Hum Mol Genet 22:3906–3919
Ma H, Thapa A, Morris L, Redmond TM, Baehr W, Ding XQ (2014) Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration. Proc Natl Acad Sci U S A 111:3602–3607
Ma H, Butler MR, Thapa A, Belcher J, Yang F, Baehr W, Biel M, Michalakis S, Ding XQ (2015) cGMP/protein kinase G signaling suppresses inositol 1,4,5-trisphosphate receptor phosphorylation and promotes endoplasmic reticulum stress in photoreceptors of cyclic nucleotide-gated channel-deficient mice. J Biol Chem 290:20880–20892
Ma H, Yang F, Butler MR, Belcher J, Redmond TM, Placzek AT, Scanlan TS, Ding XQ (2017) Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. FASEB J 31(8):3425–3438
Mears AJ, Kondo M, Swain PK, Takada Y, Bush RA, Saunders TL, Sieving PA, Swaroop A (2001) Nrl is required for rod photoreceptor development. Nat Genet 29:447–452
Ng L, Hurley JB, Dierks B, Srinivas M, Salto C, Vennstrom B, Reh TA, Forrest D (2001) A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nat Genet 27:94–98
Ng L, Hernandez A, He W, Ren T, Srinivas M, Ma M, Galton VA, St Germain DL, Forrest D (2009) A protective role for type 3 deiodinase, a thyroid hormone-inactivating enzyme, in cochlear development and auditory function. Endocrinology 150:1952–1960
Ng L, Lyubarsky A, Nikonov SS, Ma M, Srinivas M, Kefas B, St Germain DL, Hernandez A, Pugh EN Jr, Forrest D (2010) Type 3 deiodinase, a thyroid-hormone-inactivating enzyme, controls survival and maturation of cone photoreceptors. J Neurosci 30:3347–3357
Redmond TM, Yu S, Lee E, Bok D, Hamasaki D, Chen N, Goletz P, Ma JX, Crouch RK, Pfeifer K (1998) Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet 20:344–351
Yang F, Ma H, Butler M, Redmond TM, Boye SL, Hauswirth WW, Ding XQ (2016) Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. FASEB J 30(12):4313–4325
Acknowledgments
We thank Dr. T. Michael Redmond (NEI/NIH) for the Rpe65 −/− mouse line and Dr. Anand Swaroop (NEI/NIH) for the Nrl −/− mouse line. We thank Dr. P. Reed Larsen (the Brigham and Women’s Hospital) for human DIO3 cDNA. We thank the Imaging Core Facility of the Department of Cell Biology at OUHSC for technical assistance.
This work was supported by grants from the National Eye Institute (P30EY021725, P30EY021721, R01EY019490, and R21EY024583); the Research to Prevent Blindness for an unrestricted grant to the University of Florida, Department of Ophthalmology; the Foundation Fighting Blindness; and the Knights Templar Eye Foundation.
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Yang, F., Ma, H., Boye, S.L., Hauswirth, W.W., Ding, XQ. (2018). Overexpression of Type 3 Iodothyronine Deiodinase Reduces Cone Death in the Leber Congenital Amaurosis Model Mice. In: Ash, J., Anderson, R., LaVail, M., Bowes Rickman, C., Hollyfield, J., Grimm, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 1074. Springer, Cham. https://doi.org/10.1007/978-3-319-75402-4_16
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DOI: https://doi.org/10.1007/978-3-319-75402-4_16
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