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

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

doi:10.1172/jci.insight.150898

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.

Highlights

Postmitotic neuronal cell populations are sensitive to the effects of aging, as they are unable to undergo mitosis and regenerate [1]
Metabolite profiling of the neural retina showed a decrease in TCA cycle intermediates in the arRP preclinical mouse model
Because metabolic dysregulation has been shown to play a key role during age-related neurodegenerative diseases, we examined the arRP neural retina for the relative abundance of precise TCA cycle intermediates and additional metabolites at 1 month of age compared with WT controls (Figure 1H)

Summary

Introduction

Postmitotic neuronal cell populations are sensitive to the effects of aging, as they are unable to undergo mitosis and regenerate [1]. Studies have shown that mitochondrial dysfunction, impaired glucose metabolism, and abnormal aerobic glycolysis play key roles in age-related neurodegenerative diseases, such as Parkinson’s disease, Huntington’s disease, age-related macular dystrophy, and Alzheimer’s disease [2,3,4,5]. These studies suggest that it is critical for the metabolic environment to be properly maintained in neuronal cells in order to preserve cellular health. Because retinal degenerative diseases have this high genetic heterogeneity, mutations in different genes can lead to the same clinical manifestation of disease This suggests that there are common mechanisms underlying photoreceptor degeneration unrelated to the causative genetic mutation. Targeting these common cellular pathways, such as cellular metabolism, that are affected during neurodegenerative disease progression can lead to cost-effective therapeutic options for patients that do not rely on treating the individual genetic mutation

Methods

Results

Conclusion