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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.
Highlights
The rod and cone photoreceptor (PR) cells are the most abundant cell types in the human retina, with ~6.4 million cones and up to 125 million rods per adult retina [1]
The outer segment (OS) of the PR can be considered as a highly specialized cilium responsible for the conversion of light stimuli into electrical signals, known as the phototransduction cascade. This cascade requires a tremendous amount of energy as well as a continuous OS protein turnover to maintain cellular homeostasis
In many inherited retinal diseases (IRDs) this balance is disrupted leading to protein accumulation in the inner segment (IS) and to PR cell death
Summary
The rod and cone photoreceptor (PR) cells are the most abundant cell types in the human retina, with ~6.4 million cones and up to 125 million rods per adult retina [1]. The shed OS tips are subsequently phagocytosed by the retinal pigment epithelium (RPE) cells, which is the highest active phagocytic process in our body [9,10] Because of this highly active protein turnover, a mutation in a gene encoding a protein involved in this machinery most often leads to PR cell death, a classical hallmark of many inherited retinal diseases (IRDs). There is a high interest in pharmacological agents with a broad range of disease targets To discover such agents, a growing number of studies have focused on a common phenomenon seen in many IRDs before the actual death of rods and cones: the accumulation and/or misfolding of proteins in the inner segment of the photoreceptors [21]. We will explain how potential therapeutic agents directed against these branches might slow down or even arrest the dramatic blinding conditions, supported by findings of PN modulators in other research disciplines
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