Melo, E;
Oertle, P;
Trepp, C;
Meistermann, H;
Burgoyne, T;
Sborgi, L;
Cabrera, AC;
... Iacone, R; + view all
(2017)
HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model.
EBioMedicine
10.1016/j.ebiom.2017.12.011.
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Abstract
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss. The protein HtrA1 is enriched in retinal pigment epithelial (RPE) cells isolated from AMD patients and in drusen deposits. However, it is poorly understood how increased levels of HtrA1 affect the physiological function of the RPE at the intracellular level. Here, we developed hfRPE (human fetal retinal pigment epithelial) cell culture model where cells fully differentiated into a polarized functional monolayer. In this model, we fine-tuned the cellular levels of HtrA1 by targeted overexpression. Our data show that HtrA1 enzymatic activity leads to intracellular degradation of tubulin with a corresponding reduction in the number of microtubules, and consequently to an altered mechanical cell phenotype. HtrA1 overexpression further leads to impaired apical processes and decreased phagocytosis, an essential function for photoreceptor survival. These cellular alterations correlate with the AMD phenotype and thus highlight HtrA1 as an intracellular target for therapeutic interventions towards AMD treatment.
| Type: | Article |
|---|---|
| Title: | HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ebiom.2017.12.011 |
| Publisher version: | http://doi.org/10.1016/j.ebiom.2017.12.011 |
| Language: | English |
| Additional information: | Copyright © 2017 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Age-related macular degeneration, Cell stiffness, Disease modelling, HtrA serine peptidase 1, Mechanical properties, Phagocytic activity, Polarized human retinal, pigmented epithelium |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10041162 |
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