NAD+ and sirtuins in retinal degenerative diseases: A look at future therapies

Abstract

Retinal degenerative diseases are a major cause of morbidity in modern society because visual impairment significantly decreases the quality of life of patients. A significant challenge in treating retinal degenerative diseases is their genetic and phenotypic heterogeneity. However, despite this diversity, many of these diseases share a common endpoint involving death of light-sensitive photoreceptors. Identifying common pathogenic mechanisms that contribute to photoreceptor death in these diverse diseases may lead to a unifying therapy for multiple retinal diseases that would be highly innovative and address a great clinical need. Because the retina and photoreceptors, in particular, have immense metabolic and energetic requirements, many investigators have hypothesized that metabolic dysfunction may be a common link unifying various retinal degenerative diseases. Here, we discuss a new area of research examining the role of NAD⁺ and sirtuins in regulating retinal metabolism and in the pathogenesis of retinal degenerative diseases. Indeed, the results of numerous studies suggest that NAD⁺ intermediates or small molecules that modulate sirtuin function could enhance retinal metabolism, reduce photoreceptor death, and improve vision. Although further research is necessary to translate these findings to the bedside, they have strong potential to truly transform the standard of care for patients with retinal degenerative diseases.

Keywords: Metabolism; Mitochondria; NAD(+); Neurodegeneration; Retinal degeneration; Sirtuins.

Figure 1.

Schematic depicting the structural organization of the neurosensory retina and its location in the eye. The retina consists of numerous neuronal cell types, including rod and cone photoreceptors, bipolar cells, retinal ganglion cells, horizontal cells, and amacrine cells.

Figure 2.

Although nicotinamide adenine dinucleotide (NAD⁺) can be synthesized via numerous pathways, including de novo synthesis followed by the Preiss-Handler pathway, the pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT) is the dominant mammalian pathway and has been shown to be essential in numerous cell types. NAMPT catalyzes the formation of nicotinamide mononucleotide (NMN) from nicotinamide (NAM), which is then converted to NAD⁺ by NMN adenylyltransferases 1–3 (NMNAT1–3).

Figure 3.

(A–C) At 3 months, mice with monoallelic Nampt deletion from rod photoreceptors (Nampt^−rod/WT) did not exhibit any retinal dysfunction compared to Nampt^F/WT controls based on their scotopic a-wave, scotopic b-wave, or photopic b-wave amplitudes (N=6–7/group; 2-way mixed ANOVA). (D–F) Likewise, there was no significant difference in retinal function at 6 months of age (N=6–7/group; 2-way mixed ANOVA). Graphs depict mean ± S.E.M (A–F).

Figure 4.

(A) Representative blot demonstrating that retinas from 3-week-old Nampt^−rod/-rod mice displayed more PARylation compared to those from Nampt^F/F littermate controls. (B) PARP inhibition with either ABT-888 (+A), BYK 49187 (+B), or both (+A+B) in 661W photoreceptor cells treated with the NAMPT inhibitor FK866 (+FK) partially rescued reductive capacity at 24 hours (N=23–27/group; 1-way ANOVA with Tukey post-hoc test). (C) Likewise, PARP inhibition partially improved cell survival at 48 hours (N=24/group; 1-way ANOVA with Tukey post-hoc test). Graphs depict mean + S.E.M (B-C). (* P < .05; ** P < .01; *** P < .001; AU: arbitrary units; red asterisks indicate significant differences compared to the vehicle-treated group; blue asterisks indicate significant differences compared to the FK866-treated group).

Figure 5.

(A-C) Intraperitoneal injections of the PARP inhibitor ABT-888 (20 mg/kg body weight) beginning at postnatal day 5 (P5) partially protected Nampt^−rod/-rod mice from retinal dysfunction compared to vehicle-treated Nampt^−rod/-rod mice based on scotopic a-wave, scotopic b-wave, and photopic b-wave amplitudes (N=8/group; 2-way mixed ANOVA). (D-F) ABT-888 had no significant effect on retinal function in Nampt^F/F mice based on scotopic a-wave, scotopic b-wave, and photopic b-wave amplitudes (N=3–4/group; 2-way mixed ANOVA). Graphs depict mean + or – S.E.M. (A-C) or mean ± S.E.M (D-F) (* P < .05; ** P < .01).

Figure 6.

We propose that decreased retinal NAD⁺ (middle panel) and consequent sirtuin dysfunction (bottom panel) contribute to photoreceptor dysfunction and death in multiple retinal degenerative diseases (top panel). Future therapies directed towards enhancing NAD⁺ availability (middle panel) and/or restoring optimal sirtuin function (bottom panel) may thus have efficacy for preventing blindness regardless of the underlying disease etiology.