Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy

Perrault, Isabelle; Hanein, Sylvain; Zanlonghi, Xavier; Serre, Valérie; Nicouleau, Michaël; Defoort-Delhemmes, Sabine; Delphin, Nathalie; Fares-Taie, Lucas; Gerber, Sylvie; Xerri, Olivia; Edelson, C.; Goldenberg, Alice; Duncombe, A.; Meur, G. Le; Hamel, C.; Silva, Eduardo D.; Nitschké, Patrick; Calvas, Patrick; Münnich, Arnold; Roche, Olivier; Dollfus, Hélène; Kaplan, Josseline; Rozet, Jean–Michel

doi:10.1038/ng.2357

Cited by 119 publications

(94 citation statements)

References 15 publications

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“…RPE cannot survive long-term deficiency of NAD + (37, 38), and a mutation in nicotinamide nucleotide adenylyltransferase 1 (NMNAT1), the enzyme that converts NMN into NAD + , causes severe retinal degeneration in humans (39)(40)(41). We have shown that, when oxidative stress is excessive, PARP depletes NAD + .…”

Section: Discussionmentioning

confidence: 99%

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Yanagida

Knight

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

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The retinal pigment epithelium (RPE) is a monolayer of pigmented cells that requires an active metabolism to maintain outer retinal homeostasis and compensate for oxidative stress. Using 13 C metabolic flux analysis in human RPE cells, we found that RPE has an exceptionally high capacity for reductive carboxylation, a metabolic pathway that has recently garnered significant interest because of its role in cancer cell survival. The capacity for reductive carboxylation in RPE exceeds that of all other cells tested, including retina, neural tissue, glial cells, and a cancer cell line. Loss of reductive carboxylation disrupts redox balance and increases RPE sensitivity to oxidative damage, suggesting that deficiencies of reductive carboxylation may contribute to RPE cell death. Supporting reductive carboxylation by supplementation with an NAD + precursor or its substrate α-ketoglutarate or treatment with a poly(ADP ribose) polymerase inhibitor protects reductive carboxylation and RPE viability from excessive oxidative stress. The ability of these treatments to rescue RPE could be the basis for an effective strategy to treat blinding diseases caused by RPE dysfunction.reductive carboxylation | RPE | metabolism | age-related macular degeneration | oxidative stress T he retinal pigment epithelium (RPE) is a monolayer of postmitotic cells situated between the photoreceptors of the retina and the choroidal blood supply. The interaction of the RPE and photoreceptors is critical to maintaining vision. Functions of the RPE include phagocytosis of shed photoreceptor outer segments, recycling of retinoids, production and secretion of cytokines and chemokines, and mediating the exchange of nutrients and metabolites between the choroid and photoreceptors (1, 2). RPE cells provide crucial metabolic support for the retina.RPE dysfunction can lead to photoreceptor death and retinal degenerative disease, such as age-related macular degeneration (AMD), which is the leading cause of irreversible vision loss in the elderly human population (3-5). RPE cells are exposed to ongoing oxidative stress from the combined effects of light, choroidal O 2 , polyunsaturated fatty acids, and retinoids (6). The resulting impairment in RPE energy metabolism and function by oxidative stress is one likely mechanism for the pathogenesis of AMD (3, 7-11).Mitochondria support the active energy metabolism of the RPE (10-12). A recent report showed that RPE is less stable and less able to support the retina when it is forced to rely on glycolytic rather than mitochondrial metabolism (13). Another recent report supports the importance of mitochondria in RPE by showing that bolstering mitochondrial activity makes these cells more resilient to oxidative damage (14).In mitochondria, citrate can be generated from acetyl CoA and oxaloacetate as part of the TCA cycle. However, under hypoxic conditions, some cells also produce citrate via reductive carboxylation of α-ketoglutarate (αKG) through the action of NADPH-dependent isocitrate dehydrogenases (IDH) (15-17)....

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Section: Discussionmentioning

confidence: 99%

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Yanagida

Knight

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

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“…It is important to note, beyond their neuronal roles, Nmnats also have obligate roles in NAD + metabolism and multiple cellular processes across species (Zhai et al, 2009;Lin et al, 2010). Very recent reports show Nmnat1 mutations cause Leber congenital amaurosis (LCA), highlighting its importance in retinal degenerative diseases in humans (Chiang et al, 2012;Falk et al, 2012;Koenekoop et al, 2012;Perrault et al, 2012).…”

Section: Wldmentioning

confidence: 99%

Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila

Rallis

2012

Journal of Cell Science

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SummaryAxon degeneration is observed at the early stages of many neurodegenerative conditions and this often leads to subsequent neuronal loss. We previously showed that inactivating the c-Jun N-terminal kinase (JNK) pathway leads to axon degeneration in Drosophila mushroom body (MB) neurons. To understand this process, we screened candidate suppressor genes and found that the Wallerian degeneration slow (Wld S ) protein blocked JNK axonal degeneration. Although the nicotinamide mononucleotide adenylyltransferase (Nmnat1) portion of Wld S is required, we found that its nicotinamide adenine dinucleotide (NAD + ) enzyme activity and the Wld S N-terminus (N70) are dispensable, unlike axotomy models of neurodegeneration. We suggest that Wld S -Nmnat protects against axonal degeneration through chaperone activity. Furthermore, ectopically expressed heat shock proteins (Hsp26 and Hsp70) also protected against JNK and Nmnat degeneration phenotypes. These results suggest that molecular chaperones are key in JNK-and Nmnat-regulated axonal protective functions.

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“…Nmnat1 has the most robust enzymatic activity of the * This work was supported by a Grant-in-aid for Young Scientists (A) three isoforms (13). A recent genetic study revealed that Nmnat1 gene mutations cause Leber congenital amaurosis, a rare hereditary blindness (15)(16)(17)(18). Nmnat1 is also identified as a fusion gene with Ube4b in Wallerian degeneration slow (WldS) mice, which exhibit drastic delays in injured axonal clearance (19).…”

mentioning

confidence: 99%

Deficiency of Nicotinamide Mononucleotide Adenylyltransferase 3 (Nmnat3) Causes Hemolytic Anemia by Altering the Glycolytic Flow in Mature Erythrocytes

Hikosaka

Ikutani²,

Shito³

et al. 2014

Journal of Biological Chemistry

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Background: Nmnat3 is considered a mitochondria-localized NAD synthesis enzyme. However, its physiological function in vivo remains unclear. Results: Loss of Nmnat3 results in drastic depletion of the NAD pool and stalls the glycolytic flow in mature erythrocytes. Conclusion: Nmnat3 deficiency causes splenomegaly and hemolytic anemia in mice. Significance: This report reveals the essential role of Nmnat3 in mature erythrocytes.

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Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy

Cited by 119 publications

References 15 publications

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila

Deficiency of Nicotinamide Mononucleotide Adenylyltransferase 3 (Nmnat3) Causes Hemolytic Anemia by Altering the Glycolytic Flow in Mature Erythrocytes

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