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Published on: December 7, 2021
Deletion of Protein Phosphatase 2A Accelerates Retinal Degeneration in GRK1- and Arr1-Deficient Mice
Alexander V Kolesnikov1, Jennings Luu1,2, Hui Jin2
1Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California, United States.
Purpose:
Light detection in retinal rod photoreceptors is initiated by activation of the visual pigment rhodopsin. A critical, yet often-overlooked, step enabling efficient perception of light is rhodopsin dephosphorylation mediated by protein phosphatase 2A (PP2A). PP2A deficiency has been reported to impair rhodopsin regeneration after phosphorylation by G protein receptor kinase 1 (GRK1) and binding of arrestin (Arr1), thereby delaying rod dark adaptation. However, its effects on the viability of photoreceptors in the absence of GRK1 and Arr1 remain unclear. Here, we investigated the effects of PP2A deficiency in the absence of GRK1 or Arr1, both of which have been implicated in Oguchi disease, a form of night blindness.
Methods:
Rod-specific mice lacking the predominant catalytic Cα-subunit of PP2A were crossed with the Grk1-/- or Arr1-/- strains to obtain double knockout lines. Rod photoreceptor viability was analyzed in histological cross-sections of the retina stained with hematoxylin and eosin, and rod function was evaluated by ex vivo electroretinography.
Results:
PP2A deficiency alone did not impair photoreceptor viability up to 12 months of age. Retinal degeneration was more pronounced in rods lacking GRK1 compared to rods lacking Arr1, and degeneration was accelerated in both Grk1-/- or Arr1-/- strains where PP2A was also deleted. In Arr1-/- mice, rod maximal photoresponse amplitudes were reduced by 80% at 3 months, and this diminution was enhanced further with concomitant PP2A deficiency.
Conclusions:
These results suggest that although PP2A is not required for the survival of rods, its deletion accelerates the degeneration induced by the absence of either GRK1 or Arr1.
Insights
Protein phosphatase 2A (PP2A) deficiency accelerates photoreceptor degeneration in mice lacking GRK1 or Arr1, key proteins implicated in night blindness. PP2A is not essential for rod survival but exacerbates existing genetic defects.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Light detection in retinal rod photoreceptors involves rhodopsin activation and dephosphorylation.
- Protein phosphatase 2A (PP2A) mediates rhodopsin dephosphorylation, a critical step for efficient light perception.
- PP2A deficiency can delay rod dark adaptation by impairing rhodopsin regeneration.
Purpose of the Study:
- To investigate the effects of PP2A deficiency on photoreceptor viability in the absence of GRK1 or Arr1.
- To understand the role of PP2A in retinal degeneration associated with GRK1 or Arr1 deficiency.
- To explore the genetic interactions between PP2A, GRK1, and Arr1 in the context of night blindness.
Main Methods:
- Generation of double knockout mouse lines by crossing PP2A-deficient mice with Grk1-/- or Arr1-/- strains.
- Histological analysis of retinal cross-sections to assess rod photoreceptor viability.
- Ex vivo electroretinography to evaluate rod function.
Main Results:
- PP2A deficiency alone did not affect photoreceptor viability up to 12 months.
- Retinal degeneration was more severe in Grk1-/- rods than Arr1-/- rods.
- Deletion of PP2A accelerated degeneration in both Grk1-/- and Arr1-/- mice.
- Concomitant PP2A deficiency further reduced photoresponse amplitudes in Arr1-/- mice.
Conclusions:
- PP2A is not essential for rod photoreceptor survival.
- PP2A deficiency exacerbates retinal degeneration caused by the absence of GRK1 or Arr1.
- These findings highlight the complex interplay of proteins involved in visual pigment processing and photoreceptor health.
