New insights into retinoid metabolism and cycling within the retina

In the paper

“RPE65 converts all-trans retinyl-ester to 11-cis retinol (Jin et al., 2005; Moiseyev et al., 2005; Redmond et al., 2005)”

What the sources say

• ?Not checked — no full text of the sourcecites Jin et al., 2005 source
• Supported

  The paper explicitly states that RPE65 converts all-trans retinyl ester to 11-cis retinol in the Fig. 6 caption (Discussion). The Discussion also concludes that RPE65 is the enzyme responsible for this isomerohydrolase activity. (LLM, conf=0.95)

  cites Moiseyev et al., 2005 source
• Supported

  The introductory passage in our copy (labelled Abstract; page unavailable) identifies all-trans-retinyl esters as the substrate for the isomerohydrolase and 11-cis-retinol as its product. The Abstract and Discussion identify RPE65 as having a catalytic role in that reaction, in conjunction with LRAT. (LLM, conf=0.92)

  cites Redmond et al., 2005 source

In the paper

“In the RPE, RPE65 is the accepted isomerohydrolase that converts all-trans retinyl-ester to 11-cis retinol (Jin et al., 2005; Moiseyev et al., 2005; Redmond et al., 2005).”

What the sources say

• ?Not checked — no full text of the sourcecites Jin et al., 2005 source
• Supported

  The Discussion concludes that RPE65 is the enzyme responsible for isomerohydrolase activity. The Fig. 6 model identifies all-trans retinyl ester as its substrate and 11-cis retinol as its product in the RPE visual cycle. The supplied passages do not give page numbers. (LLM, conf=0.94)

  cites Moiseyev et al., 2005 sourceExperimental — accuracy not yet measured
• Supported

  The Abstract describes conversion of all-trans-retinyl esters to 11-cis-retinol in the RPE visual cycle and identifies RPE65 as the isomerohydrolase. The Discussion concludes that RPE65 has an enzymatic role in this reaction, working with LRAT, which supplies its substrate. (LLM, conf=0.93)

  cites Redmond et al., 2005 sourceExperimental — accuracy not yet measured

In the paper

“Recent evidence suggests the existence of a second retinoid visual cycle within the vertebrate retina functioning in parallel with the classic visual cycle to specifically support rapid cone pigment regeneration (Figure 5; for reviews, see (Muniz et al., 2007; Wang and Kefalov, 2011; Wolf, 2004)).”

What the sources say

• Partly supported

  The discussion of the cone cycle (section C, page not provided) reports evidence from cone-dominated chicken retina that it supports rapid cone pigment regeneration. But section D-3 says whether this retinal cone cycle coexists with the classic RPE cycle in duplex retinas remains to be examined; the paper does not establish parallel operation across vertebrate retinas. (LLM, conf=0.84)

  cites Muniz et al., 2007 sourceExperimental — accuracy not yet measured
• Supported

  Section 3 describes evidence for a second, cone-specific retinoid cycle in the retina that could rapidly supply recycled chromophore. Section 6.4 reports that the retinal and classic RPE cycles work simultaneously, increasing cone sensitivity and speeding dark adaptation. (LLM, conf=0.93)

  cites Wang and Kefalov, 2011 source
• ?Not checked — no full text of the sourcecites Wolf, 2004 source

In the paper

“In the murine RPE, we found a marked agreement between the MALDI images of A2E and the fluorescence of lipofuscin in the RPE.”

What the sources say

• Supported

  The Discussion states that there was “marked agreement” between A2E MALDI images and lipofuscin fluorescence in mouse RPE. It notes that the agreement was not perfect and was strongest where A2E levels were high. (LLM, conf=0.94)

  cites Grey et al., 2011 source

In the paper

“Taken together, these pieces of evidence have led to the proposal that bis-retinoid precursors of lipofuscin, such as A2PE, form in the photoreceptor OS from all-trans retinal that is escaping reduction to retinol (Katz and Redmond, 2001; Katz and Robinson-Jr, 2002; Sparrow et al., 2010).”

What the sources say

• ?Not checked — no full text of the sourcecites Katz and Redmond, 2001
• ?Not checked — no full text of the sourcecites Katz and Robinson-Jr, 2002 source
• Supported

  The section on photoreceptor origins reports A2PE formation in isolated outer segments and proposes that its biosynthesis begins there through reactions with all-trans-retinal. It also says all-trans-retinal is normally reduced to all-trans-retinol before transfer to the RPE, consistent with the proposal that retinal used to form A2PE escapes that reduction. The supplied copy gives no page number. (LLM, conf=0.91)

  cites Sparrow et al., 2010 source

In the paper

“These findings are in agreement with the data obtained from the tissue punch study (Bhosale et al., 2009), and demonstrate that lipofuscin fluorescence is not an adequate monitor of A2E in the human eye.”

What the sources say

• Partly supported

  The Discussion (page unavailable) says noninvasive quantitative A2E measurements in humans are difficult to perform reliably. The tissue-punch Results (page unavailable) quantify A2E by HPLC, but the paper does not compare those measurements with lipofuscin fluorescence or establish that fluorescence is an inadequate monitor of A2E. (LLM, conf=0.78)

  cites Bhosale et al., 2009 sourceExperimental — accuracy not yet measured

In the paper

“Second, bis-retinoids constitute the major extractable component of lipofuscin (Kim et al., 2007; Sparrow et al., 2012).”

What the sources say

• Partly supported

  The Discussion identifies bisretinoids as RPE lipofuscin pigments and says the all-trans-retinal dimer series is the most abundant of the lipofuscin chromophores characterized in Abcr−/− mice. It does not establish that bisretinoids constitute the major extractable component of lipofuscin generally; the abundance finding is limited to characterized chromophores in that mouse model. (LLM, conf=0.84)

  cites Kim et al., 2007 sourceExperimental — accuracy not yet measured
• Supported

  Section 2.1 states that all isolated and characterized constituents of RPE lipofuscin are bisretinoid pigments. The Conclusions likewise describe RPE lipofuscin as a mixture of bisretinoids, supporting the claim about its extractable components. (LLM, conf=0.90)

  cites Sparrow et al., 2012 source

In the paper

“Cones in Irbp-/- mice were found to be retinoid-deficient under photopic conditions in two studies (Parker et al., 2009), leading to the proposal that 11-cis retinol supplies are disrupted in the absence of IRBP.”

What the sources say

• Supported

  The Results section reports that photopic ERGs were used to test for 11-cis retinal deficiency in Irbp−/− cones and that 9-cis retinal treatment restored their responses. The Discussion explicitly describes the cones as retinoid-deficient. This supports deficiency, rather than a complete absence of retinoids. (LLM, conf=0.91)

  cites Parker et al., 2009 source

In the paper

“studies regarding retinoid analogues have shown that the binding constraints of the various rod and cone opsins are quite different.”

In the paper

“Our recent findings that RPE65, the proposed isomerase in the RPE, is present within cones (Tang et al., 2011a; Tang et al., 2011b)”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Tang et al., 2011a
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Tang et al., 2011b

In the paper

“The cone-derived 661W cells (Tan et al., 2004) are known to have retinol esterase activity (Kanan et al., 2008), and we found that 11-cis retinol can be esterified in these cells (Tang et al., 2011a).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Tang et al., 2011a

In the paper

“Using a polyclonal anti-RPE65 antibody generated from a synthetic peptide corresponding to residues 150-164 of bovine RPE65 (NFITKVNPETLETIK) (Redmond and Hamel, 2000), we showed localization of RPE65 in the OS of cones of the wild-type mice (Figure 6) (Tang et al., 2011b).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Tang et al., 2011b

In the paper

“We have recently found RPE65 to also be localized in the OS of human cones (Figure 7) (Tang et al., 2011a).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Tang et al., 2011a

In the paper

“In vitro studies using the expressed protein demonstrated that DES1 has isomerase activity.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Kaylor et al., 2012

In the paper

“We have conducted a preliminary evaluation of RPE65 staining in cones of the cone-dominant Anolis lizard and found, surprisingly, that RPE65 is localized to the IS, specifically within the paraboloid (Figure 8).”

In the paper

“Interestingly, like RPE65 (Redmond et al., 2010), DES1 is not specific in forming 11-cis retinol, but also generates 13-cis and 9-cis retinol as well.”

What the sources say

• ?Not checked — no full text of the sourcecites Redmond et al., 2010 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Kaylor et al., 2012

In the paper

“11-cis retinal is generally not as tightly bound in cone pigments as it is in rhodopsin.”

In the paper

“We have found that mouse strains with higher levels of cone RPE65 are more efficient at synthesizing cone pigments than those with less of the protein (Tang et al., 2011b).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Tang et al., 2011b

In the paper

“More recently, it has been shown directly that 11-cis retinol can indeed regenerate cone pigments within the cells by microspectrophotometry (Ala-Laurila et al., 2009).”

What the sources say

• ?Not checked — no full text of the sourcecites Ala-Laurila et al., 2009 source

In the paper

“The compound was originally proposed to be toxic to bleached rods due to increased desensitization, but now has been shown to be unable to form pigment in rods (Ala-Laurila et al., 2009).”

What the sources say

• ?Not checked — no full text of the sourcecites Ala-Laurila et al., 2009 source

In the paper

“cone pigments release retinal at a much faster rate (Chen et al., 2012b; Das et al., 2004; Hunt et al., 2009).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Chen et al., 2012b
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Das et al., 2004
• ?Not checked — no full text of the sourcecites Hunt et al., 2009 source

In the paper

“Interestingly, the level of RPE65 within cones across different strains of mice appears to be inversely related to the level of RPE65 present within the RPE (Tang et al., 2011b).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Tang et al., 2011b

In the paper

“The distribution of oxidized forms of A2E, which are proposed to be more harmful than A2E itself (Ben-Shabat et al., 2002a), followed closely that of A2E but at much reduced levels.”

In the paper

“Contrary to the murine models, the distribution of A2E in the human eyes did not correlate with lipofuscin fluorescence (Figure 12, D-F), regardless of age.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Ablonczy et al., 2012b

In the paper

“Age and the higher accumulation of A2E in the Abca4-/- model increased the correlation of lipofuscin and A2E (Figure 12, A&B).”

In the paper

“Although the quantity of A2E changed with age and strain, the fraction of oxidized A2E to unoxidized A2E was constant (0.17 ± 0.03 oxygen per A2E).”

In the paper

“In Nrl-/- photoreceptors as well as cones, formation of retinol after bleaching occurs more rapidly than in rods.”

In the paper

“However, A2E was most abundant in the far periphery (50-100-fold more than in the center), independent of age.”

In the paper

“Contrary to early dogma, cones are not exclusively dependent upon 11-cis retinal for visual pigment formation, but can also utilize the alcohol form 11-cis retinol.”

In the paper

“The sources of chromophore can come from the RPE as well as Müller cells, at least for cone photoreceptors”

In the paper

“Further support for the existence of RPE65 in mouse cones comes from the Nrl-/- mouse, which contains elevated levels of RPE65 within the retina when compared to the wild-type mouse (Wenzel et al., 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Wenzel et al., 2007 source

In the paper

“Generation of 11-cis retinal from all-trans retinol occurs in the RPE in a process referred to as the classic visual cycle (Figure 4) (Travis et al., 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Travis et al., 2007 source

In the paper

“These data suggest that the site of entry of the chromophore may be different for rods and cones.”

In the paper

“The level of 11-cis retinal generated by the cone visual cycle synthesis appears to be insufficient to promote cone survival.”

In the paper

“These results suggested that the 9-methyl group of retinal was critical in the fast deactivation of only M/LWS cone pigments.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Das et al., 2004

In the paper

“the absence of RPE65 abolishes the generation of 11-cis retinoids in the mammalian eye (Redmond et al., 1998).”

What the sources say

• ?Not checked — no full text of the sourcecites Redmond et al., 1998 source

In the paper

“As isomerization of the retinal/retinol does not occur within the cones, RPE65 is not functioning as an isomerase within the cone.”

In the paper

“Thus, the role of RPE65 in cones remains unresolved, but there is no evidence for this protein acting as an isomerase in the cone.”

In the paper

“RT-PCR analysis of isolated salamander photoreceptors first demonstrated the presence of RPE65 mRNA in cones, but not rods (Ma et al., 1998).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Ma et al., 1998

In the paper

“Furthermore, the affinity of the antibody proved to be critical for its immunodetection (Tang et al., 2011b).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Tang et al., 2011b

In the paper

“Immunohistology showed RPE65 to be present in the OS of these cone-like photoreceptors (Figure 6, B-C) (Boyer et al., 2012b).”

What the sources say

• ?Not checked — no full text of the sourcecites Boyer et al., 2012b source

In the paper

“Müller cells and cones contain the necessary machinery for completion of the cone visual cycle.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Kaylor et al., 2012

In the paper

“In Rpe65-/- mice, the absence of 11-cis retinal also results in rapid degeneration of cones (Rohrer et al., 2005; Znoiko et al., 2005).”

What the sources say

• ?Not checked — no full text of the sourcecites Rohrer et al., 2005 source
• ?Not checked — no full text of the sourcecites Znoiko et al., 2005 source

In the paper

“RPE65 has been shown to be essential in cone function of the neural retina leucine zipper knockout (Nrl-/-) mouse (Wenzel et al., 2007), a model for a pure-cone retina (Mears et al., 2001).”

What the sources say

• ?Not checked — no full text of the sourcecites Wenzel et al., 2007 source
• ?Not checked — no full text of the sourcecites Mears et al., 2001 source

In the paper

“Consistent with this notion, mice that lack retinol dehydrogenases, the enzymes that oxidize all-trans retinol to retinal show increased A2E accumulation in the RPE (Chrispell et al., 2009; Maeda et al., 2005).”

What the sources say

• ?Not checked — no full text of the sourcecites Chrispell et al., 2009 source
• ?Not checked — no full text of the sourcecites Maeda et al., 2005 source

In the paper

“The studies are in agreement that retinoid deficiency is a likely cause for the impaired cone function in the absence of IRBP.”

In the paper

“These results are based on the finding that mice raised in the dark have the same levels of lipofuscin and lipofuscin precursors as animals raised in cyclic light.”

What the sources say

• ?Not checked — no full text of the sourcecites Boyer et al., 2012a source

In the paper

“These data indicate that 11-cis retinal may have a major role in events resulting in retinal degeneration.”

In the paper

“While it is clear that retinoids are involved in lipofuscin, recent evidence shows 11-cis retinal itself may be a major source of lipofuscin and A2E (Boyer et al., 2012a).”

What the sources say

• ?Not checked — no full text of the sourcecites Boyer et al., 2012a source

In the paper

“This surprising result challenges the existing notion that A2E and lipofuscin arise from all-trans retinal generated from the bleaching of the visual pigments.”

In the paper

“Furthermore, direct addition of 11-cis retinal to rod photoreceptors results in the generation of lipofuscin precursors in the absence of light.”

What the sources say

• ?Not checked — no full text of the sourcecites Boyer et al., 2012a source

In the paper

“However, the faster formation of retinol in cones is not simply due to the earlier availability of all-trans retinal because of its faster release from photoactivated visual pigment.”