Retinal degeneration in Aipl1-deficient mice: a new genetic model of Leber congenital amaurosis

Dyer, Michael A.; Donovan, Stacy L.; Zhang, Jiakun; Gray, Jonathan; Ortiz, Astrid; Tenney, Robert; Kong, Jian; Allikmets, Rando; Sohocki, Melanie M.

doi:10.1016/j.molbrainres.2004.10.011

Cited by 46 publications

(42 citation statements)

References 49 publications

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“…However, AIPL1 is expressed in cones transiently and is thought to be absent from adult cones (3). Two independent studies demonstrated that mice lacking AIPL1 undergo a rapid and severe retinal degeneration with both rod and cone photoreceptor loss (6,7). Although AIPL1 was not essential for the initial formation of photoreceptor cells, the photoreceptor cells were not functional, as they could not evoke any light-dependent electrical response (6).…”

Section: Leber Congenital Amaurosis (Lca)mentioning

confidence: 99%

AIPL1, a Protein Associated with Childhood Blindness, Interacts with α-Subunit of Rod Phosphodiesterase (PDE6) and Is Essential for Its Proper Assembly

Kolandaivelu

Huang

Hurley

et al. 2009

Journal of Biological Chemistry

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Mutations in the gene coding for AIPL1 cause Leber congenital amaurosis (LCA), a severe form of childhood blindness. The severity in disease is reflected in the complete loss of vision and rapid photoreceptor degeneration in the retinas of mice deficient in AIPL1. Our previous observations suggest that rod photoreceptor degeneration in retinas lacking AIPL1 is due to the massive reduction in levels of rod cGMP phosphodiesterase (PDE6) subunits (␣, ␤, and ␥). To date, the crucial link between AIPL1 and the stability of PDE6 subunits is not known. In this study using ex vivo pulse label analysis, we demonstrate that AIPL1 is not involved in the synthesis of PDE6 subunits. However, ex vivo pulse-chase analysis clearly shows that in the absence of AIPL1, rod PDE6 subunits are rapidly degraded by proteasomes. We further demonstrate that this rapid degradation of PDE6 is due to the essential role of AIPL1 in the proper assembly of synthesized individual PDE6 subunits. In addition, using a novel monoclonal antibody generated against AIPL1, we show that the catalytic subunit (␣) of PDE6 associates with AIPL1 in retinal extracts. Our studies establish that AIPL1 interacts with the catalytic subunit (␣) of PDE6 and is needed for the proper assembly of functional rod PDE6 subunits. Leber congenital amaurosis (LCA)2 is an early childhood blinding disease that affects the retina. At a very young age, children affected with LCA lack both scotopic and photopic visual response implying both rod and cone photoreceptors dysfunction (1). To date, mutations in 14 genes, including the Aipl1 gene have been linked to this disease (1, 2). A recent study showed that an adult LCA patient with a mutation in Aipl1 has no visual response (3). In addition, immunohistochemistry using rod markers showed that the patient had no rod photoreceptors. Although some remnants of cone photoreceptors remained, the outer segments were completely missing, suggesting a degeneration of both rod and cone photoreceptors in this LCA patient.AIPL1 is specifically expressed in retina and in the pineal gland. In retina, AIPL1 is expressed in young and adult rod photoreceptors (4, 5). However, AIPL1 is expressed in cones transiently and is thought to be absent from adult cones (3). Two independent studies demonstrated that mice lacking AIPL1 undergo a rapid and severe retinal degeneration with both rod and cone photoreceptor loss (6, 7). Although AIPL1 was not essential for the initial formation of photoreceptor cells, the photoreceptor cells were not functional, as they could not evoke any light-dependent electrical response (6). These results are consistent with the disease characteristics of LCA (8). Our previous studies show that before degeneration, rod PDE6 activity and the levels of PDE6 protein are drastically reduced in the absence of AIPL1 (6). In addition to the knockout mouse, an AIPL1 knockdown mouse was created in which AIPL1 expression was reduced to 20 -25% of wild-type levels (9). The knockdown mouse showed normal development and retinal morpholo...

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Section: Leber Congenital Amaurosis (Lca)mentioning

confidence: 99%

AIPL1, a Protein Associated with Childhood Blindness, Interacts with α-Subunit of Rod Phosphodiesterase (PDE6) and Is Essential for Its Proper Assembly

Kolandaivelu

Huang

Hurley

et al. 2009

Journal of Biological Chemistry

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“…Animal models are available for modeling some mutations, including chicken (Perrault et al, 2000), mouse (Batten et al, 2004;Dyer et al, 2004;Ramamurthy, 2004;Redmond et al, 1998;Rolling, 2004;Yang et al, 1999), dog (Aguirre et al, 1998), and zebrafish (Stiebel-Kalish et al, 2012), but there is clearly a need for in vitro models that would allow exploration of pathological mechanisms in vitro and could be used in a search for treatment. Induced pluripotent stem cells (iPSCs) produced by genetic reprogramming of somatic cells from human donors could be of interest, because of a clinical phenotype or an identified disease-related mutation (Takahashi et al, 2007), and may be a unique tool to meet those challenges.…”

Section: Introductionmentioning

confidence: 99%

Human Induced Pluripotent Stem Cells As a Tool to Model a Form of Leber Congenital Amaurosis

Lustremant

Habeler

Plancheron

et al. 2013

Cellular Reprogramming

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Our purpose was to investigate genes and molecular mechanisms involved in patients with Leber congenital amaurosis (LCA) and to model this type of LCA for drug screening. Fibroblasts from two unrelated clinically identified patients with a yet undetermined gene mutation were reprogrammed to pluripotency by retroviral transduction. These human induced pluripotent stem cells (hiPSCs) were differentiated into neural stem cells (NSCs) that mimicked the neural tube stage and retinal pigmented epithelial (RPE) cells that could be targeted by the disease. A genome-wide transcriptome analysis was performed with Affymetrix Exon Array GeneChip(®), comparing LCA-hiPSCs derivatives to controls. A genomic search for alteration in all genes known to be involved in LCA revealed a common polymorphism on the GUCY2D gene, referenced as the LCA type I (OMIM *600179 and #204000), but the causative gene remained unknown. The hiPSCs expressed the key pluripotency factors and formed embryoid bodies in vitro containing cells originating from all three germ layers. They were successfully differentiated into NSC and RPE cells. One gene, NNAT, was upregulated in LCA cell populations, and three genes were downregulated, GSTT1, TRIM61 and ZNF558, with potential correlates for molecular mechanisms of this type of LCA, in particular for protein degradation and oxidative stress. The two LCA patient-specific iPSC lines will contribute to modeling LCA phenotypes and screening candidate drugs.

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“…AIPL1 is a chaperone protein, involved in the assembly and/or translocation of PDE to the outer segments of both rod and cone photoreceptors, 63 and in its absence photoreceptor cells are lost very rapidly in both humans 64 and mice. 65 In contrast to b-PDE-deficient mice, however, Aipl1 À/À mice are highly amenable to gene supplementation therapy, even though the defect involves both rods and cones. Subretinal injection of an AAV2/8 vector carrying the mouse or human AIPL1 gene into 10-day-old Aipl1 À/À mice, restores the translocation of PDE to the outer segments, rescues ERG activity to 50% of normal levels after 4 weeks, and substantially prolongs the survival of the photoreceptor cells, 66,67 resulting in preservation of approximately four layers of photoreceptors after 5 months.…”

Section: Progressive Photoreceptor Defectsmentioning

confidence: 99%

Gene supplementation therapy for recessive forms of inherited retinal dystrophies

Smith¹,

Bainbridge²,

Ali³

2011

Gene Ther

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Over the last decade, gene supplementation therapy for inherited retinal degeneration has come of age. Early proof-of-concept studies in animal models of disease showed modest, but genuine improvements in retinal function and/or survival. Further development of the vectors used for gene transfer to the retina has led to better treatment efficacy in a wide variety of animal models, leading in 2008 to the initiation of three clinical trials for Leber congenital amaurosis caused by retinal pigment epithelium 65 deficiency. The results from these trials suggest that the treatment of inherited retinal dystrophy by gene therapy can be safe and effective. Here, we examine the progress of gene supplementation therapy in the retina, and discuss the potential for using gene therapy to treat different forms of inherited retinal degeneration.

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Retinal degeneration in Aipl1-deficient mice: a new genetic model of Leber congenital amaurosis

Cited by 46 publications

References 49 publications

AIPL1, a Protein Associated with Childhood Blindness, Interacts with α-Subunit of Rod Phosphodiesterase (PDE6) and Is Essential for Its Proper Assembly

AIPL1, a Protein Associated with Childhood Blindness, Interacts with α-Subunit of Rod Phosphodiesterase (PDE6) and Is Essential for Its Proper Assembly

Human Induced Pluripotent Stem Cells As a Tool to Model a Form of Leber Congenital Amaurosis

Gene supplementation therapy for recessive forms of inherited retinal dystrophies

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