Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease

Abstract

The light sensing outer segments of photoreceptors (PRs) are renewed every ten days due to their high photoactivity, especially of the cones during daytime vision. This demands a tremendous amount of energy, as well as a high turnover of their main biosynthetic compounds, membranes, and proteins. Therefore, a refined proteostasis network (PN), regulating the protein balance, is crucial for PR viability. In many inherited retinal diseases (IRDs) this balance is disrupted leading to protein accumulation in the inner segment and eventually the death of PRs. Various studies have been focusing on therapeutically targeting the different branches of the PR PN to restore the protein balance and ultimately to treat inherited blindness. This review first describes the different branches of the PN in detail. Subsequently, insights are provided on how therapeutic compounds directed against the different PN branches might slow down or even arrest the appalling, progressive blinding conditions. These insights are supported by findings of PN modulators in other research disciplines.

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…This result suggests that the toxicity of GNGT1-deficiency is due to an excess of improperly assembled GNB1, which is targeted for degradation but exceeds the capacity of the proteasome [171]. This observation supports the proteostasis network model of PR degeneration [154].…”

“…By contrast, the effect of the Gln344Ter variant (Table S1), which is correctly folded but includes sequence extensions at the C-terminus that interfere with export to the OS [151], as well as the graded effect of heterozygous or homozygous knockout alleles Rho tm1Jlem and Rho tm1Phm [152,153] or the premature truncation mutant Arg107Ter (Table S1), provides evidence that a steady flow of RHO to the OS is essential for PR cell viability. These observations fit an emerging view that a proteostasis network, incorporating not only cellular stress pathways but also protein trafficking and degradation, regulates the cellular protein balance to ensure viability [147,154]. According to this view, a failure to sort vesicles bearing RHO from the Golgi to the periciliary membrane, or a partial or complete loss of the protein, leads to protein imbalance in the IS.…”

Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects

“…The copyright holder for this this version posted September 18, 2022. ; https://doi.org/10.1101/2022.09.14.22279917 doi: medRxiv preprint diseases (111), reserpine and its derivatives have clinical potential for gene-agnostic therapies.…”

Molecular Therapies for Inherited Retinal Diseases—Current Standing, Opportunities and Challenges

“…One example is the dominant-negative effect of mutations in RHO , which leads to the disruption of outer segments in the photoreceptor cell [158]. The manipulation of proteostasis mechanisms such as the heat-shock response (HSR) or unfolded protein response could be a good therapeutic target in order to alleviate misfolding diseases (e.g., targeted up-regulation of these pathways to reduce aggregation of proteins such as rhodopsin) [159]. This could be achieved either by the administration of drugs that restore proteostasis (e.g., pharmacological chaperones, kosmotropes, molecular chaperones or autophagy inducers) or by targeting key molecules in the photoreceptor proteostasis network [160,161].…”