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 3

Citrate supplementation prolongs photoreceptor cell survival and visual function in the preclinical model of arRP.

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Citrate supplementation prolongs photoreceptor cell survival and visual ...
(A) Representative average ERG traces for arRP mice (black) and arRP mice treated with citrate (blue) recorded at a 2.5 log cd•s/m2 flash intensity. (B) Quantification of the a-wave (C) and b-wave amplitude at 1 month of age shows citrate treatment causing a rescue in the b-wave response but no significant increase in a-wave response. (D) A similar trend was seen at 2 months of age, with no significant increase in a-wave amplitude (E) but a significant rescue of the b-wave response of arRP mice treated with citrate. (F) Representative average ERG traces for arRP mice and arRP mice treated with citrate recorded at a –1.1 log cd•s/m2 flash intensity. (G) Quantification of the b-wave amplitudes at 1 month (H) and 2 months of age. n ≥ 5 eyes. (I) Histology of the arRP retinas treated with citrate compared with untreated arRP retinas at both 1 and (J) 2 months of age. Scale bar: 50 μm. (K and L) Morphometric quantification of ONL thickness spanning from the ONH. n = 3 eyes each group, with multiple counts per eye. Analyzed by multiple 2-tailed t tests with the Holm-Sidak method to correct for multiple comparisons. (M) Mass spectrometry for the relative abundance of TCA cycle intermediates in retinas from untreated arRP mice and citrate-treated arRP mice at 1 month 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 < 0.001; ****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; TCA, tricarboxylic acid.