Late-onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1.

Autor: Chekuri A; Shiley Eye Institute, University of California San Diego, San Diego, CA, USA., Zientara-Rytter K; Division of Biological Sciences, University of California San Diego, San Diego, CA, USA., Soto-Hermida A; Shiley Eye Institute, University of California San Diego, San Diego, CA, USA., Borooah S; Shiley Eye Institute, University of California San Diego, San Diego, CA, USA., Voronchikhina M; Shiley Eye Institute, University of California San Diego, San Diego, CA, USA., Biswas P; Shiley Eye Institute, University of California San Diego, San Diego, CA, USA., Kumar V; Shiley Eye Institute, University of California San Diego, San Diego, CA, USA., Goodsell D; Integrative Structural and Computational Biology (ISCB), Scripps Research Institute, San Diego, CA, USA., Hayward C; Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Shaw P; Shiley Eye Institute, University of California San Diego, San Diego, CA, USA., Stanton C; Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Garland D; Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA., Subramani S; Division of Biological Sciences, University of California San Diego, San Diego, CA, USA., Ayyagari R; Shiley Eye Institute, University of California San Diego, San Diego, CA, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2019 Dec; Vol. 18 (6), pp. e13011. Date of Electronic Publication: 2019 Aug 05.
DOI: 10.1111/acel.13011
Abstrakt: Late-onset retinal degeneration (L-ORD) is an autosomal dominant macular degeneration characterized by the formation of sub-retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L-ORD results from mutations in the C1q-tumor necrosis factor-5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L-ORD pathology, we used a human cDNA library yeast two-hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM-Ch) from wild-type (Wt), heterozygous S163R Ctrp5 mutation knock-in (Ctrp5 S163R/wt ), and homozygous knock-in (Ctrp5 S163R/S163R ) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C-terminal PDZ-binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R-CTRP5 protein also binds to HTRA1 but is resistant to HTRA1-mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM-Ch of Ctrp5 S163R/S163R and Ctrp5 S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L-ORD pathology.
(© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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