HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model.

Melo, Esther and Oertle, Philipp and Trepp, Carolyn and Meistermann, Hélène and Burgoyne, Thomas and Sborgi, Lorenzo and Cabrera, Alvaro Cortes and Chen, Chia-Yi and Hoflack, Jean-Christophe and Kam-Thong, Tony and Schmucki, Roland and Badi, Laura and Flint, Nicholas and Ghiani, Zeynep Eren and Delobel, Fréderic and Stucki, Corinne and Gromo, Giulia and Einhaus, Alfred and Hornsperger, Benoit and Golling, Sabrina and Siebourg-Polster, Juliane and Gerber, Francoise and Bohrmann, Bernd and Futter, Clare and Dunkley, Tom and Hiller, Sebastian and Schilling, Oliver and Enzmann, Volker and Fauser, Sascha and Plodinec, Marija and Iacone, Roberto. (2018) HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model. EBioMedicine, 27. pp. 258-274.

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Official URL: https://edoc.unibas.ch/59183/

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller)
UniBasel Contributors:Hiller Odermatt, Sebastian
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Jul 2018 16:48
Deposited On:03 Jul 2018 16:48

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