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 6

Disease pathophysiology and metabolic analysis of an autosomal dominant preclinical model of RP.

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Disease pathophysiology and metabolic analysis of an autosomal dominant ...
(A) Histology of the retina for a WT control retina, a homozygous adRP mouse at 1 month of age, and the heterozygous adRP mouse at 4 months of age. Scale bar: 50 μm. (B) Representative average ERG traces from a 2.5 log cd•s/m2 flash intensity setting shows no difference in visual function in the heterozygous adRP mouse model (black) at 1 month of age compared with a WT control (purple), (C) but shows a reduction in visual response in the adRP mouse by 4 months of age. (D) Quantification at 4 months of age shows a significant reduction in visual response for the adRP mice compared with WT controls in both the a-wave (E) and b-wave amplitudes. (F) Representative average ERG traces recorded at a –1.1 log cd•s/m2 flash intensity. (G) Quantification of the b-wave response shows a reduction in the adRP mice compared with the WT mice. n ≥ 8 eyes. (H) Mass spectrometry for the relative abundance of TCA cycle intermediates in the retinas from WT and adRP mice at 3 months of age. n = 10 retinas. ERG and mass spectrometry data analyzed by student’s t test. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001. 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; ERG, electroretinogram; TCA, tricarboxylic acid.