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 7

Citrate and α-KG provide photoreceptor resilience against death and prolong visual function during adRP disease.

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Citrate and α-KG provide photoreceptor resilience against death and prol...
(A) Histology of the untreated and the adRP retina treated with either α-KG or citrate. (B) Quantification of photoreceptor nuclei thickness, spanning from the ONH to either direction. n ≥ 3 eyes. (C) Representative ERG traces for adRP mice (black) and adRP mice treated with α-KG (red) or citrate (blue) at a 2.5 log cd•s/m2 flash intensity. (D) Quantification of the a-wave and (E) b-wave amplitude. (F) Representative ERG traces at a –1.1 log cd•s/m2 flash intensity. (G) Quantification of the b-wave amplitude. n ≥ 8 eyes. (H) Histology of the untreated and the adRP retina treated with α-KG or citrate. Scale bar: 50 μm. (I) Morphometric quantification of ONL thickness spanning from the ONH. n ≥ 3 eyes. Statistical analysis by 1-way ANOVA (B) or 2-way ANOVA with Tukey’s multiple comparisons test (D, E, G, and I). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Red and blue asterisks reflect significance of α-KG–treated and citrate-treated mice, respectively, in comparison with untreated controls. α-KG, α-ketoglutarate; adRP, autosomal dominant retinitis pigmentosa; GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; IS/OS, inner and outer segments; RPE, retinal pigment epithelium; ONH, optic nerve head; ERG, electroretinogram.