Deficiency Disrupts Photoreceptor Viability and Synaptic Integrity in a Choroideremia Mouse Model

Choroideremia, an X-linked retinal dystrophy causing progressive vision loss, arises from deficient Rab escort protein-1 (REP1), critical for the prenylation of Rab proteins. The precise mechanisms linking REP1 dysfunction to retinal degeneration remain unclear. Here, we generated conditional REP1 knockout mice to model choroideremia and dissect REP1' s role in retinal homeostasis. Histological analysis revealed severe photoreceptor (PR) layer thinning (91.2 ± 2.34 µm vs. 188.1 ± 3.46 µm in controls) by postnatal day 30, accompanied by disrupted synaptic architecture in the outer plexiform layer (OPL). Electroretinogram (ERG) demonstrated profound visual dysfunction, with scotopic a-wave and b-wave amplitudes reduced by 69.6% and 86.7%, respectively, indicating PR and perhaps bipolar cell (BC) impairment. RNA-Sequencing and immunofluorescence labeling showed downregulation of PR, synaptic, and phototransduction-related molecules as well as disrupted structural integrity of PRs. Transmission electron microscopy (TEM) revealed ultrastructural synaptic defects, including shortened synaptic ribbons and loss of invaginated triads. Our findings establish an essential role for REP1 in maintaining PR viability and synaptic connectivity. Furthermore, we also provide mechanistic insights into the progression of choroideremia associated with the activation of microglia mediated by the NF-?B pathway, suggesting that neuro-immune is one of the potential therapeutic targets for preserving retinal circuitry in patients with choroideremia. Overall design: RNA-seq profiling of C57BL/6J wildtype mice and conditional REP1 knockout mice to model choroideremia at P30.