Differential rhodopsin mislocalization in rod photoreceptor synapses from P23H-Rho-RFP and rd10 retinitis pigmentosa mice

Presenters/Authors(s)

Sophie Crowder, Michael Robichaux, Samantha Thompson

Abstract or Description

 Retinitis pigmentosa (RP) is a genetic eye disease that causes degeneration of rod photoreceptors in the retina and vision loss. Rhodopsin (Rho) is the protein that initiates the phototransduction visual pathway in rod photoreceptors. Rods constantly transport Rho to the outer segment compartment, but RP mutations often cause Rho mistrafficking, which leads to rod degeneration. The P23H misfolding mutation to Rho is the most common human RP mutation, and mutant P23H-Rho protein mislocalizes to rod presynaptic terminals, where rods form synapses to propagate the light signals to inner retina neurons. Another mouse model of RP, rd10, has normally folded Rho, but Rho protein still mislocalizes throughout rods including at the presynaptic terminals. In this study we compared the P23H-Rho-RFP with rd10 mice to determine if there are morphological or protein expression differences in the synaptic region across the 2 RP models. Super-resolution microscopy and electron microscopy were used to visualize mislocalized Rho in the mutant presynaptic terminals and synaptic protein expression levels were measured. In the P23H-Rho-RFP rods, the Rho was exclusively localized inside the terminals, as expanded folds of ER membranes, along with significant changes in presynaptic protein levels. In the rd10 rods, Rho was mislocalized to the plasma membrane of terminals and there were no significant protein differences. Our work demonstrates that an essential ER secretory pathway regulates the protein content of rod synaptic terminals, and that this system is disrupted only by misfolding Rho mutations (including P23H-Rho) and not when Rho is mislocalized at the plasma membrane.