Identification of Active Retinaldehyde Dehydrogenase Isoforms in the Postnatal Human Eye

Harper, Angelica R.; Wiechmann, Allan F.; Moiseyev, Gennadiy; Xing, Jian; Summers, Jody A.

doi:10.1371/journal.pone.0122008

Cited by 25 publications

(18 citation statements)

References 33 publications

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“…In humans suffering from malnutrition, vitamin A deficiency results in night blindness and photoreceptor cell damage and subsequent degeneration (Wiseman et al, 2017). Retinaldehyde is oxidized into retinoic acid (RA) by retinaldehyde dehydrogenase (RALDH), an enzyme that is expressed across retinal cells (Luo et al, 2006;Harper et al, 2015). Binding of RA to its nuclear receptor (RAR α/β/γ ) releases it from co-repressor (CoR), allowing it to form a heterodimeric complex with retinoid orphan receptors (RXR α/β/γ ) that can bind DNA and act as a transcriptional activator and enhancer.…”

Section: Retinoic Acid-dependent Signaling Is Essential For Remodelingmentioning

confidence: 99%

Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

2020

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Vision impairment and blindness in humans are most frequently caused by the degeneration and loss of photoreceptor cells in the outer retina, as is the case for age-related macular degeneration, retinitis pigmentosa, retinal detachment and many other diseases. While inner retinal neurons survive degeneration, they undergo fundamental pathophysiological changes, collectively known as “remodeling.” Inner retinal remodeling downstream to photoreceptor death occurs across mammalian retinas from mice to humans, independently of the cause of degeneration. It results in pervasive spontaneous hyperactivity and membrane hyperpermeability in retinal ganglion cells, which funnel all retinal signals to the brain. Remodeling reduces light detection in vision-impaired patients and precludes meaningful vision restoration in blind individuals. In this review, we summarize current hypotheses proposed to explain remodeling and their potential medical significance highlighting the important role played by retinoic acid and its receptor.

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Section: Retinoic Acid-dependent Signaling Is Essential For Remodelingmentioning

confidence: 99%

Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

2020

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“…However, the functional role of these enzymes in the adult eye and cornea has not been explored, primarily due to the fact that deletion of Aldh1a2 is lethal early in development (Niederreither et al, 1999), whereas Aldh1a3 null mutants die at birth (Dupé et al, 2003); Aldh1a1 mutants are viable but do not exhibit obvious eye defects (Fan et al, 2003). Recent studies on expression patterns of RA signaling components in the human eye show that ALDH1A enzymes are expressed in adult eye tissues including cornea, conjunctiva, and choroid (Nezzar et al, 2007; Harper et al, 2015). Also, ALDH1A1 expression in the cornea and lens has been proposed to protect inner ocular tissues from ultraviolet radiation and reactive oxygen-induced damage as ALDH1A1 can metabolize reactive aldehydes as well as retinaldehyde (Lassen et al, 2007).…”

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confidence: 99%

Endogenous retinoic acid signaling is required for maintenance and regeneration of cornea

Kumar

Dollé

Ghyselinck

et al. 2017

Experimental Eye Research

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Retinoic acid (RA) is a biologically active metabolite of vitamin A (retinol) that serves as an important signaling molecule in orchestrating diverse developmental processes including multiple roles during ocular development. Loss-of-function studies using gene knockouts of RA-synthesizing enzymes encoded by Aldh1a1, Aldh1a2, and Aldh1a3 (also known as Raldh1, Raldh2, and Raldh3) have provided valuable insight into how RA controls eye morphogenesis including corneal development, however it is unclear whether endogenous RA is required for maintenance and regeneration of adult cornea. Here, we investigated the role of Aldh1a genes in the adult cornea using a novel conditional Aldh1a1,2,3-flox/flox;Rosa26-CreERT2 loss-of-function mouse model to determine the biological function of RA. Our findings indicate that loss of RA synthesis results in corneal thinning characterized by reduced thickness of the stromal layer, impaired corneal epithelial cell proliferation, and increased apoptosis. Corneal thinning in Aldh1a-deficient mice was significantly rescued by RA administration, indicating an important role of endogenous RA signaling in adult corneal homeostasis and regeneration. Thus, Aldh1a1,2,3-flox/flox;Rosa26-CreERT2 mice provide a useful model for investigating the mechanistic role of RA signaling in adult corneal maintenance and could provide new insights into therapeutic approaches for controlling corneal repair to prevent vision loss.

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“…This suggests that an overabundance of RAL might underlie the increase in RA signaling in degenerating retinas. The enzymatic machinery necessary for synthesizing RAL is expressed only in RPE, rods and cones, and Müller glial cells (23), but RALDH is expressed in nearly all retinal neurons (24,25). Hence, in principle, enhanced RA signaling in RGCs could result from the diffusion of either the substrate RAL, or the product RA, from the outer to the inner retina.…”

Section: Discussionmentioning

confidence: 99%