Melo, Esther; Oertle, Philipp; Trepp, Carolyn Mary; Meistermann, Hélène; Burgoyne, Thomas; Sborgi, Lorenzo; Cabrera, Alvaro Cortes; Chen, Chia-Yi; Hoflack, Jean-Christophe; Kam-Thong, Tony; Schmucki, Roland; Badi, Laura; Flint, Nicholas; Ghiani, Zeynep Eren; Delobel, Fréderic; Stucki, Corinne; Gromo, Giulia; Einhaus, Alfred; Hornsperger, Benoit; Golling, Sabrina; ... (2018). HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model. EBioMedicine, 27, pp. 258-274. Elsevier 10.1016/j.ebiom.2017.12.011
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ophthalmology 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Augenklinik > Forschungsgruppe Augenheilkunde |
Graduate School: |
Graduate School for Cellular and Biomedical Sciences (GCB) |
UniBE Contributor: |
Trepp, Carolyn Mary, Enzmann, Volker |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2352-3964 |
Publisher: |
Elsevier |
Language: |
English |
Submitter: |
Volker Enzmann |
Date Deposited: |
19 Jan 2018 16:48 |
Last Modified: |
05 Dec 2022 15:09 |
Publisher DOI: |
10.1016/j.ebiom.2017.12.011 |
PubMed ID: |
29269042 |
Uncontrolled Keywords: |
Age-related macular degeneration Cell stiffness Disease modelling HtrA serine peptidase 1 Mechanical properties Phagocytic activity Polarized human retinal, pigmented epithelium |
BORIS DOI: |
10.7892/boris.108510 |
URI: |
https://boris.unibe.ch/id/eprint/108510 |
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