ESR14: Pharmacological protein folding manipulations of ABCA4 mutations
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Davide Piccolo
I am Davide Piccolo, original from Naples (IT), a passionate scientist trying to do good science. I have a master's degree in Biology and I pursued my master's thesis at TIGEM. On June 28, 2023 I received my PhD degree in Cellular and Molecular Neuroscience. The experience in the StarT consortium was life changing, both scientifically and personally. I have met people from all over the world and learned so much from them. The programme was extremely organised and enjoyable and the science behind was great! I am currently grant co-investigator at UCL, Institute of Ophthalmology. |
Abstract
The majority of ABCA4 mutations found in STGD1 are missense mutations. Many of those that have been studied in detail (for example R602W, L541P) lead to protein misfolding, endoplasmic reticulum (ER) retention and protein degradation, leading to loss of function. Missense mutations in the related ABC transporter CFTR are also prone to misfolding and respond well to pharmacological manipulation to improve folding and restore function. P8-UCL has a great deal of experience of manipulating mutant rhodopsin folding, degradation and aggregation both in cells and in vivo. Therefore, we believe that ABCA4 will also be amenable to pharmacological protein folding manipulation. ESR14 will test pharmacological approaches that are effective for CFTR and mutant rhodopsin for their ability to rescue mutant ABCA4 folding, traffic and function. ESR14 will use a combination of heterologous expression of ABCA4 mutants in cell culture and human iPSC derived 3D retinal organoids that express endogenous mutated ABCA4 for these studies to provide direct proof of concept for pharmacological manipulation of ABCA4.Paragraph. Haz clic aquí para editar.
The majority of ABCA4 mutations found in STGD1 are missense mutations. Many of those that have been studied in detail (for example R602W, L541P) lead to protein misfolding, endoplasmic reticulum (ER) retention and protein degradation, leading to loss of function. Missense mutations in the related ABC transporter CFTR are also prone to misfolding and respond well to pharmacological manipulation to improve folding and restore function. P8-UCL has a great deal of experience of manipulating mutant rhodopsin folding, degradation and aggregation both in cells and in vivo. Therefore, we believe that ABCA4 will also be amenable to pharmacological protein folding manipulation. ESR14 will test pharmacological approaches that are effective for CFTR and mutant rhodopsin for their ability to rescue mutant ABCA4 folding, traffic and function. ESR14 will use a combination of heterologous expression of ABCA4 mutants in cell culture and human iPSC derived 3D retinal organoids that express endogenous mutated ABCA4 for these studies to provide direct proof of concept for pharmacological manipulation of ABCA4.Paragraph. Haz clic aquí para editar.
