Aipl1-KO Mouse

Aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) is a photoreceptor-specific molecular co-chaperone. It interacts with molecular chaperones HSP90 and HSP70 to facilitate the correct folding and assembly of retinal cGMP phosphodiesterase (PDE6) holoenzyme, which is crucial for the phototransduction cascade [2]. Mutations in AIPL1 are mainly associated with autosomal recessive Leber congenital amaurosis (LCA), a severe early-onset blinding disease [2].

Mouse models have revealed that AIPL1 is important for the stability and function of heteromeric phosphodiesterase 6 (PDE6) [1]. Zebrafish models, where there are two aipl1 genes (aipl1a and aipl1b), show that cone-specific aipl1b is required for cone survival, and Aipl1 is needed for the stability of Pde6c and Gc3 in cones [4]. In human patient-derived models like retinal organoids, AIPL1 gene replacement therapy effectively rescued molecular features of AIPL1-associated LCA4, such as restoring the loss of retinal phosphodiesterase 6 and reducing elevated cGMP levels [3].

In conclusion, AIPL1 is essential for the proper folding and assembly of PDE6, playing a critical role in photoreceptor function and survival. Research using genetic models, including mouse, zebrafish, and human-derived retinal organoids, has revealed its significance in maintaining the integrity of the phototransduction cascade and its association with Leber congenital amaurosis, providing insights into potential therapeutic strategies for this severe retinal disease [1,2,3,4].

References:

1. Kolandaivelu, Saravanan, Ramamurthy, Visvanathan. . AIPL1 protein and its indispensable role in cone photoreceptor function and survival. In Advances in experimental medicine and biology, 801, 43-8. doi:10.1007/978-1-4614-3209-8_6. https://pubmed.ncbi.nlm.nih.gov/24664679/

2. Sacristan-Reviriego, Almudena, van der Spuy, Jacqueline. . The Leber Congenital Amaurosis-Linked Protein AIPL1 and Its Critical Role in Photoreceptors. In Advances in experimental medicine and biology, 1074, 381-386. doi:10.1007/978-3-319-75402-4_47. https://pubmed.ncbi.nlm.nih.gov/29721967/

3. Sai, Hali, Ollington, Bethany, Rezek, Farah O, Leung, Amy, van der Spuy, Jacqueline. 2024. Effective AAV-mediated gene replacement therapy in retinal organoids modeling AIPL1-associated LCA4. In Molecular therapy. Nucleic acids, 35, 102148. doi:10.1016/j.omtn.2024.102148. https://pubmed.ncbi.nlm.nih.gov/38439910/

4. Iribarne, Maria, Nishiwaki, Yuko, Nakamura, Shohei, Oguri, Eri, Masai, Ichiro. 2017. Aipl1 is required for cone photoreceptor function and survival through the stability of Pde6c and Gc3 in zebrafish. In Scientific reports, 7, 45962. doi:10.1038/srep45962. https://pubmed.ncbi.nlm.nih.gov/28378769/