Mice deficient in the Vici syndrome gene <i>Epg5</i> exhibit features of retinitis pigmentosa

<p>Autophagy helps to maintain cellular homeostasis by removing misfolded proteins and damaged organelles, and generally acts as a cytoprotective mechanism for neuronal survival. Here we showed that mice deficient in the Vici syndrome gene <i>Epg5</i>, which is required for autophagosome maturation, show accumulation of ubiquitin-positive inclusions and SQSTM1 aggregates in various retinal cell types. In <i>epg5</i><sup>−/−</sup> retinas, photoreceptor function is greatly impaired, and degenerative features including progressively reduced numbers of photoreceptor cells and increased numbers of apoptotic cells in the outer nuclear layer are observed, while the morphology of other parts of the retina is not severely affected. Downstream targets of the unfolded protein response (UPR), including the death inducer DDIT3/CHOP, and also levels of cleaved CASP3 (caspase 3), are elevated in <i>epg5</i><sup>−/−</sup> retinas. Thus, apoptotic photoreceptor cell death in <i>epg5</i><sup>−/−</sup> retinas may result from the elevated UPR. Our results reveal that <i>Epg5-</i>deficient mice recapitulate key characteristics of retinitis pigmentosa and thus may provide a valuable model for investigating the molecular mechanism of photoreceptor degeneration.</p>