June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Analysis of P23H rhodopsin mislocalization in rod photoreceptor synapses during retinitis pigmentosa progression
Author Affiliations & Notes
  • Samantha Thompson
    West Virginia University, Morgantown, West Virginia, United States
  • Sophie M Crowder
    West Virginia University, Morgantown, West Virginia, United States
  • Michael Robichaux
    West Virginia University, Morgantown, West Virginia, United States
  • Footnotes
    Commercial Relationships   Samantha Thompson None; Sophie Crowder None; Michael Robichaux None
  • Footnotes
    Support  NIGMS P20GM144230
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4872. doi:
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      Samantha Thompson, Sophie M Crowder, Michael Robichaux; Analysis of P23H rhodopsin mislocalization in rod photoreceptor synapses during retinitis pigmentosa progression. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4872.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Retinitis pigmentosa (RP) is an inherited retinal neurodegenerative disease impacting rod photoreceptors - specialized neurons responsible for dim light and peripheral vision. The prevalence of RP is 1:4,000 in the United States, and the disease leads to night blindness, peripheral vision loss, and complete blindness. RP is often caused by rod photoreceptor loss due to the mistrafficking of rhodopsin (Rho), and the P23H mutation is the most common mutation in autosomal dominant RP. In multiple mouse models of RP, Rho is mislocalized to the rod synapses; however, this synaptic mislocalization, and the impact mislocalized Rho has on synaptic function has not been explored in depth. We hypothesize that RP mutations that cause Rho mislocalization to the synapse disrupt the normal secretory system for synaptic proteins leading to localized presynaptic defects in RP mutant rods.

Methods : We used a combination of structured illumination microscopy (SIM), transmission electron microscopy (TEM), and quantitative confocal microscopy to characterize the impact of Rho mislocalization on synaptic morphology and protein expression in knockin P23H-hRho-RFP mice that contain the human P23H RHO gene fused to a red fluorescent protein.

Results : SIM super-resolution analysis in P23H–hRho-RFP/+ mice showed Rho mislocalization in ~half of the rod presynaptic spherules at postnatal day(P) 30, as well as defects in the morphology of synaptic ribbons. Synaptic ribbon defects were also observed with TEM. Confocal microscopy revealed differences in the presynaptic proteins dystrophin and Bassoon between wild-type and P23H-hRho-RFP/+ mutant mice at postnatal days 30, 90, and 180. Mutant mice have reduced dystrophin levels than wild-type controls at P30 with significant increases in dystrophin and Bassoon expression at P90 and P180.

Conclusions : Our results demonstrate P23H-Rho-RFP protein is mislocalized near the ribbon synapses in rods, and that synaptic protein expression is impacted in our RP model. This could represent a form of homeostatic plasticity in the P23H-hRho-RFP/+ mouse retina to maintain function in rod synapses. As such, future studies will investigate the impact of modified presynaptic protein expression on rod function. Our goal is to determine the impact of this synaptic RP disease phenotype and how it contributes to the RP disease pathway in rods.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.


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