Replenishment of TCA cycle intermediates provides photoreceptor resilience against neurodegeneration during progression of retinitis pigmentosa
Ashley A. Rowe, Pinkal D. Patel, Ruth Gordillo, Katherine J. Wert
Ashley A. Rowe, Pinkal D. Patel, Ruth Gordillo, Katherine J. Wert
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Research Article Metabolism Ophthalmology

Replenishment of TCA cycle intermediates provides photoreceptor resilience against neurodegeneration during progression of retinitis pigmentosa

Abstract

The metabolic environment is important for neuronal cells, such as photoreceptors. When photoreceptors undergo degeneration, as occurs during retinitis pigmentosa (RP), patients have progressive loss of vision that proceeds to full blindness. Currently, there are no available treatments for the majority of RP diseases. We performed metabolic profiling of the neural retina in a preclinical model of RP and found that TCA cycle intermediates were reduced during disease. We then determined that (a) promoting citrate production within the TCA cycle in retinal neurons during disease progression protected the photoreceptors from cell death and prolonged visual function, (b) supplementation with single metabolites within the TCA cycle provided this therapeutic effect in vivo over time, and (c) this therapeutic effect was not specific to a particular genetic mutation but had broad applicability for patients with RP and other retinal degenerative diseases. Overall, targeting TCA cycle activity in the neural retina promoted photoreceptor survival and visual function during neurodegenerative disease.

Authors

Ashley A. Rowe, Pinkal D. Patel, Ruth Gordillo, Katherine J. Wert

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Figure 4

Succinate supplementation provides resilience against cell death for the photoreceptors and prolongs visual function.

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Succinate supplementation provides resilience against cell death for the...
(A) Representative average ERG traces for untreated arRP mice (black) and arRP mice treated with glutamine (green) or succinate (yellow) recorded at a 2.5 log cd•s/m2 flash intensity. (B) Quantification of the a-wave (C) and b-wave amplitude for both glutamine-treated arRP mice and succinate-treated arRP mice compared with untreated arRP mice. (D) By 2 months of age, no significant change was detected in the a-wave response for either succinate or glutamine treatment, (E) but succinate-treated arRP mice showed an increase in b-wave response. (F) Representative average ERG traces for untreated arRP mice and arRP mice treated with glutamine or succinate recorded at a –1.1 log cd•s/m2 flash intensity. (G) Quantification of the b-wave amplitude shows a significant increase for arRP mice treated with glutamine or succinate at 1 month (H) but shows no detectable increase by 2 months of age. n ≥ 5 eyes. (I) Histology of the arRP retinas treated with either glutamine or succinate compared with untreated arRP retinas at 1 (L) and 2 months of age. Scale bar: 50 μm. (J and K) Morphometric quantification of ONL thickness spanning from the ONH at 1 (M and N) and 2 months of age. n = 3 eyes each group, with multiple counts per eye. ONL Thickness was analyzed by multiple 2-tailed t tests with the Holm-Sidak method to correct for multiple comparisons. ERG data were analyzed by student’s t test. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. ERG, electroretinogram; arRP, autosomal recessive retinitis pigmentosa; GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium; ONH, optic nerve head.