| First Author | Deng WT | Year | 2018 |
| Journal | Front Mol Neurosci | Volume | 11 |
| Pages | 233 | PubMed ID | 30038560 |
| Mgi Jnum | J:281820 | Mgi Id | MGI:6380805 |
| Doi | 10.3389/fnmol.2018.00233 | Citation | Deng WT, et al. (2018) Cone Phosphodiesterase-6gamma' Subunit Augments Cone PDE6 Holoenzyme Assembly and Stability in a Mouse Model Lacking Both Rod and Cone PDE6 Catalytic Subunits. Front Mol Neurosci 11:233 |
| abstractText | Rod and cone phosphodiesterase 6 (PDE6) are key effector enzymes of the vertebrate phototransduction pathway. Rod PDE6 consists of two catalytic subunits PDE6alpha and PDE6beta and two identical inhibitory PDE6gamma subunits, while cone PDE6 is composed of two identical PDE6alpha' catalytic subunits and two identical cone-specific PDE6gamma' inhibitory subunits. Despite their prominent function in regulating cGMP levels and therefore rod and cone light response properties, it is not known how each subunit contributes to the functional differences between rods and cones. In this study, we generated an rd10/cpfl1 mouse model lacking rod PDE6beta and cone PDE6alpha' subunits. Both rod and cone photoreceptor cells are degenerated with age and all PDE6 subunits degrade in rd10/cpfl1 mice. We expressed cone PDE6alpha' in both rods and cones of rd10/cpfl1 mice by adeno-associated virus (AAV)-mediated delivery driven by the ubiquitous, constitutive small chicken beta-actin promoter. We show that expression of PDE6alpha' rescues rod function in rd10/cpfl1 mice, and the restoration of rod light sensitivity is attained through restoration of endogenous rod PDE6gamma and formation of a functional PDE6alpha'gamma complex. However, improved photopic cone responses were achieved only after supplementation of both cone PDE6alpha' and PDE6gamma' subunits but not by PDE6alpha' treatment alone. We observed a two fold increase of PDE6alpha' levels in the eyes injected with both PDE6alpha' plus PDE6gamma' relative to eyes receiving PDE6alpha' alone. Despite the presence of both PDE6gamma' and PDE6gamma, the majority of PDE6alpha' formed functional complexes with PDE6gamma', suggesting that PDE6alpha' has a higher association affinity for PDE6gamma' than for PDE6gamma. These results suggest that the presence of PDE6gamma' augments cone PDE6 assembly and enhances its stability. Our finding has important implication for gene therapy of PDE6alpha'-associated achromatopsia. |
