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 mouse to model choroideremia and dissect REP1's role in retinal homeostasis. Histological analysis revealed severe photoreceptor (PR) layer thinning by postnatal day 30, accompanied by disrupted synaptic architecture in the outer plexiform layer. Electroretinography revealed significant visual dysfunction, characterized by substantially reduced scotopic a-wave and b-wave amplitudes, 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 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 demonstrated that retinal degeneration in CHM mouse is associated with the activation of microglia mediated by the NF-κB pathway, suggesting that targeting neuroimmune is one of the potential therapies for CHM patients.