Targeting Proteostasis and Protein Quality Control in Photoreceptors Towards Therapeutic Intervention - Systems pharmacology for protein folding disorders in the retina

01/07/2017 to 30/06/2022

Inherited retinal degenerations are blinding diseases due to mutations that affect retinal cells. Depending on the inherited mutation present in the patient’s genome, degeneration can affect different retinal cell types, but in most cases, the light sensing photoreceptors are affected. A specific number of mutations leading to vision loss affect proper folding of proteins into their functional shape, which in turn causes pertinent intracellular stress. Cells are equipped with different physiological mechanisms to detect misfolding and deal with stress caused by misfolded proteins. This process, which includes a biochemical quality control, intracellular sorting and removal of defective proteins is called proteostasis. Proteostasis is critical for cell survival, as an imbalance in proteostasis for prolonged periods of time results in cell death. Photoreceptors fall short to cope with unfolded protein stress, once have to deal with misfolding of the visual pigment rhodopsin. In consequence they degenerate and gradually die off.
The project is geared towards a thorough investigation of the link between proteostasis and photoreceptor cell death. We aim at providing data that facilitate the targeting of proteostasis regulators towards development of therapies for inherited retinal degeneration.
The outcome of the project will generate a proof of concept for pharmacological intervention into IRD, facilitate future therapeutic interventions of proteostasis and provide a rationale for clinical trials of drugs that target the proteostasis network.