The integrity and organization of the human AIPL1 functional domains is critical for its role as a HSP90-dependent co-chaperone for rod PDE6

Sacristán-Reviriego, Almudena; Bellingham, James; Prodromou, Chrisostomos; Boehm, Annika N; Aichem, Annette; Kumaran, Neruban; Bainbridge, James; Michaelides, Michel; Spuy, Jacqueline van der

doi:10.1093/hmg/ddx334

Cited by 19 publications

(40 citation statements)

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“…The reduction in levels of AIPL1 www.nature.com/scientificreports www.nature.com/scientificreports/ p.Cys89Arg is likely due to misfolding of AIPL1 and consequent degradation. This finding contrasts with the exogenously overexpressed AIPL1 p.Cys89Arg and other missense mutants whose expression was similar to wild-type AIPL1 in HEK293T and COS-7 cells 9,19 . We hypothesize that this difference in mutant AIPL1 stability can be attributed to the heterologous expression system under the exogenous, strong promoter that evades endoplasmic reticulum surveillance or that photoreceptors employ more stringent quality control systems.…”

Section: Discussioncontrasting

confidence: 69%

“…The crystal structure of AIPL1-FKBP demonstrated a uniquely specialized lipid binding motif involving a conformational switch of W72 residue 18 . Additionally, AIPL1 may promote the stability of PDE6 via an interaction with HSP90, thus rescuing PDE6 from proteasomal degradation 19 . AIPL1 also interacts with the NUB1 (NEDD8 Ultimate Buster 1) cell cycle progression control protein by downregulating NEDD8 expression 20 , thus suggesting that the early onset of disease may be a result of the misregulation of photoreceptor development rather than a visual phototransduction defect.…”

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confidence: 99%

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Retinal Organoids derived from hiPSCs of an AIPL1-LCA Patient Maintain Cytoarchitecture despite Reduced levels of Mutant AIPL1

Lukovic

Castro

Kaya

et al. 2020

Sci Rep

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Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a photoreceptor-specific chaperone that stabilizes the effector enzyme of phototransduction, cGMP phosphodiesterase 6 (PDE6). Mutations in the AIPL1 gene cause a severe inherited retinal dystrophy, Leber congenital amaurosis type 4 (LCA4), that manifests as the loss of vision during the first year of life. In this study, we generated three-dimensional (3D) retinal organoids (ROs) from human induced pluripotent stem cells (hiPSCs) derived from an LCA4 patient carrying a Cys89Arg mutation in AIPL1. This study aimed to (i) explore whether the patient hiPSC-derived ROs recapitulate LCA4 disease phenotype, and (ii) generate a clinically relevant resource to investigate the molecular mechanism of disease and safely test novel therapies for LCA4 in vitro. We demonstrate reduced levels of the mutant AIPL1 and PDE6 proteins in patient organoids, corroborating the findings in animal models; however, patient-derived organoids maintained retinal cell cytoarchitecture despite significantly reduced levels of AIPL1. Hereditary retinal degenerations are clinically and genetically heterogeneous and constitute a major cause of incurable visual impairment in working age adults. Unfortunately, this group of diseases currently lacks effective treatment options. Among the divergent clinical phenotypes, Leber congenital amaurosis (LCA) accounts for ∼5% of all inherited retinopathies and is among the most severe, with patients exhibiting visual dysfunction and losing electroretinogram signals during the early years of age 1. Patients typically present nystagmus (repetitive, uncontrolled movements of the eyes), poor pupillary light response, and fundus abnormalities 2. Currently, as many as 25 genes have been identified as causing LCA (https://sph.uth.edu/retnet/) primarily in an autosomal recessive manner; however, genetic defects have not been identified in almost 30% of LCA patients 2. All known causative genes are expressed in photoreceptors and/or the retinal pigment epithelium (RPE) and associated with a wide range of functions, including phototransduction, retinoid cycling, protein trafficking, and ciliary transport. Mutations in the aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) gene lead to early onset retinal disease and account for up to 5-10% of all mutations causing LCA 3 resulting in a clinically severe form, LCA type 4 (LCA4, OMIM #604393) 4. The AIPL1 gene locates to chromosome 17, with 79 mutations identified to date as causing LCA (Human Genome Mutation Database). AIPL1 encodes a 384 amino acid protein expressed only in photoreceptors and the pineal gland 5. The protein has an FK506-binding protein (FKBP)-like domain within the N terminus, a tetratricopeptide (TPR) domain with three TPR repeats, and a primate unique proline-rich domain

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Section: Discussioncontrasting

confidence: 69%

mentioning

confidence: 99%

Retinal Organoids derived from hiPSCs of an AIPL1-LCA Patient Maintain Cytoarchitecture despite Reduced levels of Mutant AIPL1

Lukovic

Castro

Kaya

et al. 2020

Sci Rep

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“…Our functional assays thus show that the FKBP-like and TPR domains are important for both HSP90 interaction and the modulation of cGMP levels. This confirms our previously reported conclusions that the relative conformational organization and orientation of these domains is important and necessary for AIPL1 function 5 . Within the linker between the TPR domain and PRD, the c.894G>C (p.Q298H) sequence variant has been reported as a rare heterozygous change in a single patient with no second allele identified by direct sequencing of the AIPL1 gene 39 .…”

Section: Discussionsupporting

confidence: 93%

“…AIPL1 sequences were checked by Sanger sequencing (Source Bioscience). To express rod PDE6 subunits in cells, pcDNA3.1AXpress-PDE6α, pCMV-HA-PDE6β and pCMV-Myc-PDE6γ were used 5 .…”

Section: Aipl1 Sequence Variations Nomenclature and In Silico Analysismentioning

confidence: 99%

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Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration

Sacristán-Reviriego

Georgiou

et al. 2020

Sci Rep

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Disease-causing sequence variants in the highly polymorphic AIPL1 gene are associated with a broad spectrum of inherited retinal diseases ranging from severe autosomal recessive Leber congenital amaurosis to later onset retinitis pigmentosa. AIPL1 is a photoreceptor-specific co-chaperone that interacts with HSP90 to facilitate the stable assembly of retinal cGMP phosphodiesterase, PDE6. In this report, we establish unequivocal correlations between patient clinical phenotypes and in vitro functional assays of uncharacterized AIPL1 variants. We confirm that missense and nonsense variants in the FKBP-like and tetratricopeptide repeat domains of AIPL1 lead to the loss of both HSP90 interaction and PDE6 activity, confirming these variants cause LCA. In contrast, we report the association of p.G122R with milder forms of retinal degeneration, and show that while p.G122R had no effect on HSP90 binding, the modulation of PDE6 cGMP levels was impaired. The clinical history of these patients together with our functional assays suggest that the p.G122R variant is a rare hypomorphic allele with a later disease onset, amenable to therapeutic intervention. Finally, we report the primate-specific proline-rich domain to be dispensable for both HSP90 interaction and PDE6 activity. We conclude that variants investigated in this domain do not cause disease, with the exception of p.A352_P355del associated with autosomal dominant cone-rod dystrophy.

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HSP70-HSP90 Chaperone Networking in Protein-Misfolding Disease

Prodromou

Aran-Guiu²,

Oberoi³

et al. 2022

Subcellular Biochemistry

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Molecular chaperones and their associated co-chaperones are essential in health and disease as they are key facilitators of protein folding, quality control and function. In particular, the heat shock protein (HSP) 70 and HSP90 molecular chaperone networks have been associated with neurodegenerative diseases caused by aberrant protein folding. The pathogenesis of these disorders usually includes the formation of deposits of misfolded, aggregated protein. HSP70 and HSP90, plus their co-chaperones, have been recognised as potent modulators of misfolded protein toxicity, inclusion formation and cell survival in cellular and animal models of neurodegenerative disease. Moreover, these chaperone machines function not only in folding, but also in proteasome mediated degradation of neurodegenerative disease proteins. This chapter gives an overview of the HSP70 and HSP90 chaperones, and their respective regulatory co-chaperones, and explores how the HSP70 and HSP90 chaperone systems form a larger functional network and its relevance to counteracting neurodegenerative disease associated with misfolded proteins and disruption of proteostasis.

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The integrity and organization of the human AIPL1 functional domains is critical for its role as a HSP90-dependent co-chaperone for rod PDE6

Cited by 19 publications

References 47 publications

Retinal Organoids derived from hiPSCs of an AIPL1-LCA Patient Maintain Cytoarchitecture despite Reduced levels of Mutant AIPL1

Retinal Organoids derived from hiPSCs of an AIPL1-LCA Patient Maintain Cytoarchitecture despite Reduced levels of Mutant AIPL1

Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration

HSP70-HSP90 Chaperone Networking in Protein-Misfolding Disease

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