Deuterium Enrichment of Vitamin A at the C20 Position Slows the Formation of Detrimental Vitamin A Dimers in Wild-type Rodents

Kaufman, Yardana; Ma, Li; Washington, Ilyas

doi:10.1074/jbc.m110.178640

Cited by 62 publications

(73 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similar to humans, Abca4 knockout (Abca4 −/− ) mice exhibit increased rates of vitamin A dimerization and lipofuscin accumulation compared with their wild-type counterparts (17,18). Administration of C20-D 3 -vitamin A has been shown to inhibit vitamin A dimerization (19). Thus, to determine whether vitamin A dimerization was responsible for RPE lipofuscin formation, we administered a standard rodent diet to a cohort of Abca4 −/− mice (control group) and compared signatures of retinal health with another cohort, in which we replaced vitamin A in the standard diet by the same amount of C20-D 3 -vitamin A (treatment group).…”

Section: Resultsmentioning

confidence: 99%

“…As lipofuscin accumulation is a hallmark of RPE senescence, this work suggests that vitamin A dimerization is a major chemical event responsible for RPE senescence and that inhibiting dimerization may impede RPE senescence and related retinopathies. C20-D 3 -vitamin A slows the rate of vitamin A dimerization by as much as sevenfold in test tubes (19), and the rate of accumulation of orange ocular pigments and A2E by four-to sixfold in animals, but does not entirely halt the dimerization. As such, the remaining lipofuscin may result from residual dimerization of vitamin A or from other, poorly understood events that may also be responsible for lipofuscinogenesis in other tissues.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

Issa

Barnard

Herrmann

et al. 2015

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

Self Cite

102

View full text Add to dashboard Cite

Stargardt disease, an ATP-binding cassette, subfamily A, member 4 (ABCA4)-related retinopathy, is a genetic condition characterized by the accelerated accumulation of lipofuscin in the retinal pigment epithelium, degeneration of the neuroretina, and loss of vision. No approved treatment exists. Here, using a murine model of Stargardt disease, we show that the propensity of vitamin A to dimerize is responsible for triggering the formation of the majority of lipofuscin and transcriptional dysregulation of genes associated with inflammation. Data further demonstrate that replacing vitamin A with vitamin A deuterated at the carbon 20 position (C20-D 3 -vitamin A) impedes the dimerization rate of vitamin A-by approximately fivefold for the vitamin A dimer A2E-and subsequent lipofuscinogenesis and normalizes the aberrant transcription of complement genes without impairing retinal function. Phenotypic rescue by C20-D 3 -vitamin A was also observed noninvasively by quantitative autofluorescence, an imaging technique used clinically, in as little as 3 months after the initiation of treatment, whereas upon interruption of treatment, the age-related increase in autofluorescence resumed. Data suggest that C20-D 3 -vitamin A is a clinically amiable tool to inhibit vitamin A dimerization, which can be used to determine whether slowing the dimerization of vitamin A can prevent vision loss caused by Stargardt disease and other retinopathies associated with the accumulation of lipofuscin in the retina.S targardt disease, first described in 1909, is an autosomal recessive macular dystrophy affecting ∼1 in 10,000 people. The majority of people affected by the disease present with uncorrectable, decreased visual acuity during their teenage years, which most often progresses to legal blindness. To date, there is no approved intervention. Stargardt disease is marked by premature accumulation of lipofuscin in the retinal pigment epithelium (RPE), degeneration of the neuroretina, and subsequent loss of vision. The condition results from mutations in the ATPbinding cassette, subfamily A, member 4 (ABCA4) gene (1), which encodes a transmembrane flippase localized in photoreceptor outer segments. The flippase transports the phosphatidyl-ethanolamineretinaldehyde Schiff base between the cytosol and the cytoplasmic disk surfaces (2). Mutations in ABCA4 also result in retinitis pigmentosa and cone-rod dystrophy and have been linked to age-related macular degeneration (AMD) (3, 4).The accumulation of lipofuscin in the RPE is a common denominator in retinopathies associated with mutations in the ABCA4 gene. Also known as "wear and tear pigment," lipofuscin accumulates as a byproduct of cumulative damage during aging. The brown-yellow, autofluorescent, electron-dense material is also found in cells of the liver, kidney, heart muscle, adrenals, nerve, and ganglion and is considered one of the most consistent morphologic features of aging with a rate of accumulation inversely related to longevity (5, 6). In Stargardt disease, changes in RPE lipof...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

Issa

Barnard

Herrmann

et al. 2015

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

Self Cite

102

View full text Add to dashboard Cite

show abstract

“…Replacing the C20 hydrogen atoms of vitamin A with deuterium atoms (i.e. C20-D 3 -vitamin A) makes this bond harder to cleave and impedes vitamin A dimerization (14). In this study we sought to determine whether retarding the intrinsic reactivity of vitamin A to dimerize could slow lipofuscin formation in the RPE and delay changes associated with human Stargardt disease.…”

mentioning

confidence: 99%

“…In the accompanying article, we have shown that the ratedetermining step in vitamin A dimerization is the cleavage of a C20 carbon-hydrogen bond of the retinaldehyde-PE Schiff base (14). Replacing the C20 hydrogen atoms of vitamin A with deuterium atoms (i.e.…”

mentioning

confidence: 99%

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

Kaufman

Zhang

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Autosomal recessive Stargardt disease (STGD1) is a macular dystrophy resulting from mutations in the ABCA4 (ABCR) gene. The age of onset of Stargardt disease is typically 10 -20 years of age and leads in almost all cases to blindness by age 50 (1, 2). A hallmark of the disease is premature lipofuscin accumulation in the retinal pigment epithelium (RPE) 2 of the eye. The RPE is critical for the neurosensory retina homeostasis; it acts as a transport exchange system with blood capillaries and is critical for regeneration and phagocytosis of photoreceptor outer segments. It is hypothesized that when RPE lipofuscin reaches a critical level, it contributes to a decline in cell function (3-8) resulting in the degeneration of the macular region of the neurosensory retina leading to loss of central vision (9 -11).The defective gene in Stargardt, ABCA4, encodes for an outer segment rim protein (RmP). The function of RmP is to transport the all-trans-retinaldehyde-phosphatidylethanolamine (retinaldehyde-PE) Schiff base from the luminal side of the disk membrane to the cytosolic face, where retinaldehyde can then be converted back to retinol (3). In the absence of its proper transporter, the retinaldehyde-PE conjugates may react to form vitamin A dimers (A2E and ATR-dimer among others), which are then deposited in the RPE after phagocytosis of the photoreceptors outer segments. Numerous studies have demonstrated the toxicity of vitamin A dimers to cultured RPE cells and they are hypothesized to play a key role in lipofuscin formation and subsequent retinal degeneration (12, 13). Nevertheless, the exact mechanisms that lead to lipofuscin accumulation or to vision loss as a result of the impaired transport of the retinaldehyde-PE conjugates remain unclear.In the accompanying article, we have shown that the ratedetermining step in vitamin A dimerization is the cleavage of a C20 carbon-hydrogen bond of the retinaldehyde-PE Schiff base (14). Replacing the C20 hydrogen atoms of vitamin A with deuterium atoms (i.e. C20-D 3 -vitamin A) makes this bond harder to cleave and impedes vitamin A dimerization (14). In this study we sought to determine whether retarding the intrinsic reactivity of vitamin A to dimerize could slow lipofuscin formation in the RPE and delay changes associated with human Stargardt disease. To accomplish this we raised ABCA4 Ϫ/Ϫ mutant albino mice (the mouse model of human Stargardt's disease) on diets containing either C20-D 3 -vitamin A (the treated group) or vitamin A at its natural isotopic abundance (the control group) and measured the concentration of vitamin A dimers, lipofuscin and other biological markers indicative of ocular health in both groups. Treated mice exhibited an 80% reduction in A2E, a 95% reduction in ATR dimer and a 70% decrease in fundus autofluorescence at three months of age. After six months, the treated group showed fewer lipofuscin granules as visualized qualitatively by electron microscopy, and at 12 months they showed improved eye function as measured by electroretinogram (ERG). ...

show abstract

“…Recruitment is now ongoing for a phase 2 placebocontrolled study (ClinicalTrials.gov identifier: NCT02402660) that will examine tolerability and effects of ALK-001 in STGD1. As indicated by the authors, the efficiency with which native vitamin A is replaced by C20-D 3 -vitamin A remains to be determined (55). An increase in total vitamin A intake might also potentiate the drive toward bisretinoid formation (56).…”

Section: Therapeutic Approaches That Target Bisretinoid: Clinical Andmentioning

confidence: 99%

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Sparrow

2016

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

View full text Add to dashboard Cite

Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation.age-related macular degeneration | vitamin A-aldehyde adducts | bisretinoids | retinal pigment epithelium | photoreceptor cells Age-related macular degeneration (AMD) is a complex disorder that is predicted to have a growing impact on elderly populations. Although the cause of central vision loss in AMD is the progressive impairment of photoreceptor cells, the disease is generally thought to begin with dysfunctioning of retinal pigment epithelium (RPE) and adverse changes in subjacent Bruch's membrane (1, 2). The early stage of the disease is typically marked by extracellular accumulations (drusen) between RPE and Bruch's membrane. Progression to advanced disease is defined by delineated areas devoid of RPE and photoreceptor cell loss (atrophic AMD) and/or abnormal growth of blood vessels underneath RPE or within the subretinal space (neovascular AMD). AMD Risk FactorsAMD susceptibility is influenced by multiple factors of both genetic and environmental origin. Predisposing genetic factors account for 71% of the variation in disease risk among individuals (3). Currently, 52 independently associated genetic variants at 34 loci are known to account for ∼50% of AMD heritability (4). The genes implicated by these variants belong to multiple systems some of which are associated with the complement pathway, lipid metabolism, and maintenance of extracellular matrix (5, 6). Nevertheless, many individuals carrying risk variants do not develop AMD.Two loci, CFH (complement factor H; 1q31) and ARMS2/HTRA1 (age-related maculopathy susceptibility 2/high-temperature requirement factor A1; 10q26), make the greatest contribution to AMD risk. Variants at the ARMS2/HTRA1 and CFH loci significantly increase risk for progression to both the atrophic and neovascular forms of AMD, although the magnitude of the association of the ARMS2/HTRA1 risk allele is somewhat greater for the neovascular phenotype of late AMD, whereas CFH risk variants favor progression toward geogr...

show abstract

Deuterium Enrichment of Vitamin A at the C20 Position Slows the Formation of Detrimental Vitamin A Dimers in Wild-type Rodents

Cited by 62 publications

References 42 publications

Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Contact Info

Product

Resources

About