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
View: Text | PDF
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

×

Figure 1

Metabolite profiling of the neural retina shows a decrease in TCA cycle intermediates in a model of arRP.

Options: View larger image (or click on image) Download as PowerPoint
Metabolite profiling of the neural retina shows a decrease in TCA cycle ...
(A) Retinal histology shows a loss of the photoreceptors (ONL) in the arRP mouse compared with a WT control. Scale bar: 50 μm. (B) Morphometric quantification of ONL thickness spanning from the ONH as measured by number of cell nuclei in each region of the retina for a WT mouse (purple) and an untreated arRP mouse (black). 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. (C) Representative average traces from a scotopic ERG at a –1.1 log cd•s/m2 flash intensity. (D) Quantification of the b-wave amplitude shows a significant reduction in visual response for the arRP mice compared with WT controls. (E) Representative average traces from a scotopic ERG at a 2.5 log cd•s/m2 flash intensity. (F) Quantification of the a-wave amplitude shows a significant reduction in visual response for the arRP mice compared with controls. (G) Quantification of the b-wave amplitude shows a significant reduction in visual response for the arRP mice compared with controls. n = 8 eyes for WT, n = 5 eyes for arRP. (H) Mass spectrometry for the relative abundance of TCA cycle intermediates in the neural retinas from WT and arRP mice at 1 month of age. n ≥ 10 retinas. Data are represented as mean ± SEM. ERG and mass spectrometry data analyzed by student’s t test. *P < 0.05; **P < 0.01; ****P < 0.0001. TCA, tricarboxylic acid; arRP, autosomal recessive retinitis pigmentosa; ONL, outer nuclear layer; ONH, optic nerve head; GCL, ganglion cell layer; INL, inner nuclear layer; IS/OS, inner and outer segments; RPE, retinal pigment epithelium; ERG, electroretinogram.