Pathomechanisms of Inherited Retinal Degeneration and Perspectives for Neuroprotection

Abstract

The precise processes causing photoreceptor cell death in retinal degeneration (RD) are still largely unknown but are likely to follow a variety of degenerative mechanisms. While different genetic insults can trigger distinct molecular pathways, eventually these may converge into a limited number of common cell death mechanisms. These mechanisms often involve deregulation of cyclic guanosine monophosphate (cGMP)-signaling and proteostasis, which both may increase photoreceptor energy expenditure. Comprehensive information on these mechanisms may allow for targeted interventions to delay or prevent photoreceptor loss. Here, we review the current knowledge on photoreceptor degenerative mechanisms, focusing on processes triggered by aberrant cGMP-signaling, proteostasis, and energy metabolism. Afterward, we discuss how these pathways could potentially be used to treat photoreceptor degeneration, highlighting data from a number of recent studies on inhibitory cGMP analogs, proteostasis blockers, and interventions aimed at fortifying energetic status. Finally, we provide perspectives on how such experimental approaches could be translated into future clinical applications.

Figure 1.

Degenerative mechanisms in retinal degeneration (RD) and therapeutic approaches. The ensemble of cell death mechanisms leading to photoreceptor degeneration likely forms a continuum that may be structured according to the severity of the causative genetic insult. While apoptotic cell death is typically associated with retinal development, RD-causing mutations may initially affect cyclic guanosine monophosphate (cGMP)-signaling and proteostasis. Eventually, different genetic triggers may converge on excessive photoreceptor energy consumption, ultimately resulting in cell death. (PKG) Protein kinase G, (CNGC) cyclic nucleotide-gated channel, (VCP) valosin-containing protein, (PARP) poly(ADP-ribose) polymerase.