RPE65-related Leber's congenital amaurosis (LCA) is a rod-cone dystrophy whose 
clinical outcome is mainly attributed to the loss of rod photoreceptors followed 
by cone degeneration. Pathogenesis in Rpe65(-/-) mice is characterized by a slow 
and progressive degeneration of rods dependent on the constitutive activation of 
unliganded opsin. We previously reported that this opsin-mediated apoptosis of 
rods was dependent on Bcl-2-apoptotic pathway and Bax-induced pro-death 
activity. In this study, we report early initial apoptosis in the newly 
differentiated retina of Rpe65(-/-) mice. Apoptotic photoreceptors were 
identified as rods and resulted from pathological phototransduction signaling. 
This wave of early apoptosis triggered Bcl-2-related pathway and Bax apoptotic 
activity, while activation of the caspases was not induced. Following cellular 
stress, multiple signaling pathways are initiated which either commit cells to 
death or trigger pro-survival responses including autophagy. We report that 
Bcl-2-related early rod apoptosis was associated with the upregulation of 
autophagy markers including chaperone-mediated autophagy (CMA) substrate 
receptor LAMP-2 and lysosomal hydrolases Cathepsin S and Lysozyme. This suggests 
that lysosomal-mediated autophagy may be triggered in response to early rod 
apoptosis in Rpe65-LCA disease. These results highlight that Rpe65-related 
primary stress induces early signaling events, which trigger 
Bax-induced-apoptotic pathway and autophagy-mediated cellular response. These 
events may determine retinal cell fate, progression and severity of the disease.