Role of Nuclear NAD in Retinal Homeostasis

Overview

Journal Adv Exp Med Biol

Specialties Biology
General Medicine

Date 2023 Jul 13

PMID 37440039

Authors

Emily E Brown

Michael J Scandura

Eric Pierce

Affiliations

Soon will be listed here.

Abstract

The retina is one of the most metabolically active tissues and maintenance of metabolic homeostasis is critical for retinal function. Nicotinamide adenine dinucleotide (NAD) is a cofactor that is required for key processes, including the electron transport chain, glycolysis, fatty acid oxidation, and redox reactions. NAD also acts as a co-substrate for enzymes involved in maintaining genomic DNA integrity and cellular homeostasis, including poly-ADP ribose polymerases (PARPs) and Sirtuins. This review highlights the importance of NAD in the retina, including the role of enzymes involved in NAD production in the retina and how NAD-consuming enzymes may play a role in disease pathology. We also suggest a cell death pathway that may be common in multiple models of photoreceptor degeneration and highlight the role that NAD likely plays in this process. Finally, we explore future experimental approaches to enhance our understanding of the role of NAD in the retina.

Citing Articles

Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism.

Gottemukkala K, Chrustowicz J, Sherpa D, Sepic S, Vu D, Karayel O Mol Cell. 2024; 84(10):1948-1963.e11.

PMID: 38759627 PMC: 7616709. DOI: 10.1016/j.molcel.2024.04.014.

References

Abad-Morales V, Wert A, Ruiz Gomez M, Navarro R, Pomares E . New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform. Int J Mol Sci. 2021; 22(5). PMC: 7956282. DOI: 10.3390/ijms22052262. View

Araki T, Sasaki Y, Milbrandt J . Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004; 305(5686):1010-3. DOI: 10.1126/science.1098014. View

Cassar S, Dunn C, Olson A, Buck W, Fossey S, Ferrell Ramos M . From the Cover: Inhibitors of Nicotinamide Phosphoribosyltransferase Cause Retinal Damage in Larval Zebrafish. Toxicol Sci. 2018; 161(2):300-309. DOI: 10.1093/toxsci/kfx212. View

Chiang P, Wang J, Chen Y, Fu Q, Zhong J, Chen Y . Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis. Nat Genet. 2012; 44(9):972-4. DOI: 10.1038/ng.2370. View

Conforti L, Janeckova L, Wagner D, Mazzola F, Cialabrini L, Di Stefano M . Reducing expression of NAD+ synthesizing enzyme NMNAT1 does not affect the rate of Wallerian degeneration. FEBS J. 2011; 278(15):2666-79. DOI: 10.1111/j.1742-4658.2011.08193.x. View

David K, Andrabi S, Dawson T, Dawson V . Parthanatos, a messenger of death. Front Biosci (Landmark Ed). 2009; 14(3):1116-28. PMC: 4450718. DOI: 10.2741/3297. View

Falk M, Zhang Q, Nakamaru-Ogiso E, Kannabiran C, Fonseca-Kelly Z, Chakarova C . NMNAT1 mutations cause Leber congenital amaurosis. Nat Genet. 2012; 44(9):1040-5. PMC: 3454532. DOI: 10.1038/ng.2361. View

Fernandes K, Mitchell K, Patel A, Marola O, Shrager P, Zack D . Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury. Exp Eye Res. 2018; 171:54-61. PMC: 5964014. DOI: 10.1016/j.exer.2018.03.007. View

Fernando F, Conforti L, Tosi S, Smith A, Coleman M . Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(s)) mouse. Gene. 2002; 284(1-2):23-9. DOI: 10.1016/s0378-1119(02)00394-3. View

10.

Gerdts J, Brace E, Sasaki Y, DiAntonio A, Milbrandt J . SARM1 activation triggers axon degeneration locally via NAD⁺ destruction. Science. 2015; 348(6233):453-7. PMC: 4513950. DOI: 10.1126/science.1258366. View

11.

Greenwald S, Brown E, Scandura M, Hennessey E, Farmer R, Du J . Mutant Nmnat1 leads to a retina-specific decrease of NAD+ accompanied by increased poly(ADP-ribose) in a mouse model of NMNAT1-associated retinal degeneration. Hum Mol Genet. 2021; 30(8):644-657. PMC: 8127407. DOI: 10.1093/hmg/ddab070. View

12.

Greenwald S, Charette J, Staniszewska M, Shi L, Brown S, Stone L . Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease. Am J Pathol. 2016; 186(7):1925-1938. PMC: 4929402. DOI: 10.1016/j.ajpath.2016.03.013. View

13.

Jadeja R, Powell F, Jones M, Fuller J, Joseph E, Thounaojam M . Loss of NAMPT in aging retinal pigment epithelium reduces NAD availability and promotes cellular senescence. Aging (Albany NY). 2018; 10(6):1306-1323. PMC: 6046249. DOI: 10.18632/aging.101469. View

14.

Kaur J, Mencl S, Sahaboglu A, Farinelli P, van Veen T, Zrenner E . Calpain and PARP activation during photoreceptor cell death in P23H and S334ter rhodopsin mutant rats. PLoS One. 2011; 6(7):e22181. PMC: 3134478. DOI: 10.1371/journal.pone.0022181. View

15.

Koenekoop R, Wang H, Majewski J, Wang X, Lopez I, Ren H . Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat Genet. 2012; 44(9):1035-9. PMC: 3657614. DOI: 10.1038/ng.2356. View

16.

Lin J, Kubota S, Ban N, Yoshida M, Santeford A, Sene A . NAMPT-Mediated NAD(+) Biosynthesis Is Essential for Vision In Mice. Cell Rep. 2016; 17(1):69-85. PMC: 5104206. DOI: 10.1016/j.celrep.2016.08.073. View

17.

Massoll C, Mando W, Chintala S . Excitotoxicity upregulates SARM1 protein expression and promotes Wallerian-like degeneration of retinal ganglion cells and their axons. Invest Ophthalmol Vis Sci. 2013; 54(4):2771-80. PMC: 3632266. DOI: 10.1167/iovs.12-10973. View

18.

Paquet-Durand F, Silva J, Talukdar T, Johnson L, Azadi S, van Veen T . Excessive activation of poly(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse. J Neurosci. 2007; 27(38):10311-9. PMC: 6672664. DOI: 10.1523/JNEUROSCI.1514-07.2007. View

19.

Perrault I, Hanein S, Zanlonghi X, Serre V, Nicouleau M, Defoort-Delhemmes S . Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy. Nat Genet. 2012; 44(9):975-7. DOI: 10.1038/ng.2357. View

20.

Sahaboglu A, Barth M, Secer E, Del Amo E, Urtti A, Arsenijevic Y . Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration. Sci Rep. 2016; 6:39537. PMC: 5177898. DOI: 10.1038/srep39537. View