Thyroid hormone (TH) signaling has been shown to regulate cone photoreceptor viability. Suppression of TH signaling with antithyroid drug treatment or by targeting iodothyronine deiodinases and TH receptors preserves cones in mouse models of retinal degeneration, including the Leber congenital amaurosis Rpe65-deficient mice. This work investigates the cellular mechanisms underlying how suppressing TH signaling preserves cones in Rpe65-deficient mice, using mice deficient in type 2 iodothyronine deiodinase (Dio2), the enzyme that converts the prohormone thyroxine to the active hormone triiodothyronine (T3). Deficiency of Dio2 improved cone survival and function in Rpe65^-^/^- and Rpe65-deficiency on a cone dominant background ( Rpe65^-^/^-/ Nrl^-^/^-) mice. Analysis of cell death pathways revealed that receptor-interacting serine/threonine-protein kinase (RIPK)/necroptosis activity was increased in Rpe65^-^/^-/ Nrl^-^/^- retinas, and Dio2 deficiency reversed the alterations. Cell-stress analysis showed that the cellular oxidative stress responses were increased in Rpe65^-^/^-/ Nrl^-^/^- retinas, and Dio2 deficiency abolished the elevations. Similarly, antithyroid drug treatment resulted in reduced RIPK/necroptosis activity and oxidative stress responses in Rpe65^-^/^-/ Nrl^-^/^- retinas. Moreover, treatment with T3 significantly induced RIPK/necroptosis activity and oxidative stress responses in the retina. This work shows that suppression of TH signaling reduces cellular RIPK/necroptosis activity and oxidative stress responses in degenerating retinas, suggesting a mechanism underlying the observed cone preservation.-Yang, F., Ma, H., Butler, M. R., Ding, X.-Q. Deficiency of type 2 iodothyronine deiodinase reduces necroptosis activity and oxidative stress responses in retinas of Leber congenital amaurosis model mice.

#	Concept	H-Index	Publications	Citations
1	Medicine	1	1	20
2	Social Sciences	1	1	20
3	Epidemiology	1	1	20
4	Psychiatry	1	1	20
5	Mental Health	1	1	20

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