TY - JOUR
T1 - Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration
AU - Wert, Katherine J.
AU - Velez, Gabriel
AU - Kanchustambham, Vijaya L.
AU - Shankar, Vishnu
AU - Evans, Lucy P.
AU - Sengillo, Jesse D.
AU - Zare, Richard N.
AU - Bassuk, Alexander G.
AU - Tsang, Stephen H.
AU - Mahajan, Vinit B.
N1 - Funding Information:
VBM and AGB are supported by NIH grants [ R01EY026682 , R01EY024665 , R01EY025225 , R01EY024698 , R21AG050437 and P30EY026877 ], and Research to Prevent Blindness (RPB), New York, NY. GV is supported by NIH grants [ F30EYE027986 and T32GM007337 ]. Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory are supported by the National Institute of Health [ 5P30EY019007 , R01EY018213 ], National Cancer Institute Core [5P30CA013696], the Research to Prevent Blindness (RPB) Physician-Scientist Award, unrestricted funds from RPB, New York, NY, USA. Foundation Fighting Blindness [ TA-NMT-0116–0692-COLU ], the Research to Prevent Blindness (RPB) Physician-Scientist Award, and unrestricted funds from RPB, New York, NY, USA. S.H.T. is a member of the RD-CURE Consortium and is supported by Kobi and Nancy Karp, the Crowley Family Fund, the Rosenbaum Family Foundation, the Tistou and Charlotte Kerstan Foundation, the Schneeweiss Stem Cell Fund, New York State [C029572], and the Gebroe Family Foundation. RNZ is supported by NSF grant CHE-1734082 .
Publisher Copyright:
© 2020
PY - 2020/2
Y1 - 2020/2
N2 - Background: Neurodegenerative diseases are incurable disorders caused by progressive neuronal cell death. Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in photoreceptor death and progresses to the loss of the entire retinal network. We previously found that proteomic analysis of the adjacent vitreous served as way to indirectly biopsy the retina and identify changes in the retinal proteome. Methods: We analyzed protein expression in liquid vitreous biopsies from autosomal recessive (ar)RP 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 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. Findings: Dietary supplementation of a single metabolite, ɑ-ketoglutarate, increased docosahexaeonic acid 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) on ɑ-ketoglutarate-treated mice revealed restoration of metabolites that correlated with our proteomic findings: uridine, dihydrouridine, and thymidine (pyrimidine and purine metabolism), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). Interpretation: This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs retinal function and provides a neuroprotective effect on the photoreceptor cells and inner retinal network. Funding: NIH grants [R01EY026682, R01EY024665, R01EY025225, R01EY024698, R21AG050437, P30EY026877, 5P30EY019007, R01EY018213, F30EYE027986, T32GM007337, 5P30CA013696], NSF grant CHE-1734082.
AB - Background: Neurodegenerative diseases are incurable disorders caused by progressive neuronal cell death. Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in photoreceptor death and progresses to the loss of the entire retinal network. We previously found that proteomic analysis of the adjacent vitreous served as way to indirectly biopsy the retina and identify changes in the retinal proteome. Methods: We analyzed protein expression in liquid vitreous biopsies from autosomal recessive (ar)RP 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 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. Findings: Dietary supplementation of a single metabolite, ɑ-ketoglutarate, increased docosahexaeonic acid 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) on ɑ-ketoglutarate-treated mice revealed restoration of metabolites that correlated with our proteomic findings: uridine, dihydrouridine, and thymidine (pyrimidine and purine metabolism), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). Interpretation: This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs retinal function and provides a neuroprotective effect on the photoreceptor cells and inner retinal network. Funding: NIH grants [R01EY026682, R01EY024665, R01EY025225, R01EY024698, R21AG050437, P30EY026877, 5P30EY019007, R01EY018213, F30EYE027986, T32GM007337, 5P30CA013696], NSF grant CHE-1734082.
KW - Desorption electrospray ionization mass spectrometry
KW - Ketogenic diet
KW - Metabolite supplementation
KW - Metabolomics
KW - TCA cycle
KW - ɑ-ketoglutarate
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U2 - 10.1016/j.ebiom.2020.102636
DO - 10.1016/j.ebiom.2020.102636
M3 - Article
C2 - 32028070
AN - SCOPUS:85078757515
SN - 2352-3964
VL - 52
JO - EBioMedicine
JF - EBioMedicine
M1 - 102636
ER -