TY - JOUR T1 - Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration JF - bioRxiv DO - 10.1101/764100 SP - 764100 AU - Katherine J. Wert AU - Gabriel Velez AU - Kanchustambham Vijayalakshmi AU - Vishnu Shankar AU - Jesse D. Sengillo AU - Richard N. Zare AU - Alexander G. Bassuk AU - Stephen H. Tsang AU - Vinit B. Mahajan Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/09/10/764100.abstract N2 - Neurodegenerative diseases are debilitating, incurable disorders caused by progressive neuronal cell death. Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in retinal photoreceptor cell death and progresses to the loss of the entire neural retinal network. We previously found that proteomic analysis of the adjacent vitreous serves as way to indirectly biopsy the neural retina and identify changes in the retinal proteome. We therefore analyzed protein expression in liquid vitreous biopsies from autosomal recessive retinitis pigmentosa (arRP) patients with PDE6A mutations and arRP mice with Pde6ɑ mutations. Proteomic analysis of retina and vitreous samples identified molecular pathways affected at the onset of photoreceptor cell death. Based on affected molecular pathways, arRP mice were treated with a ketogenic diet or metabolites involved in fatty-acid synthesis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle. Dietary supplementation of a single metabolite, ɑ-ketoglutarate, increased docosahexaeonic acid (DHA) levels, provided neuroprotection, and enhanced visual function in arRP mice. A ketogenic diet delayed photoreceptor cell loss, while vitamin B supplementation had a limited effect. Finally, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) revealed restoration of key metabolites that correlated with our proteomic findings: pyrimidine and purine metabolism (uridine, dihydrouridine, and thymidine), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs vision and provides a neuroprotective effect on the photoreceptor cells and inner retinal network.One Sentence Summary The study shows protein and metabolite pathways affected during neurodegeneration and that replenishing metabolites provides a neuroprotective effect on the retina. ER -