期刊
AGING CELL
卷 18, 期 6, 页码 -出版社
WILEY
DOI: 10.1111/acel.13011
关键词
age-related macular degeneration; CTRP5; drusen; ECM remodeling; HTRA1; L-ORD; sub-RPE deposits
资金
- Foundation Fighting Blindness
- Research to Prevent Blindness
- Edward N. & Della L. Thome memorial foundation
- [NIH-R01EY21237]
- [P30-EY22589]
- [NIH 2 RO1DK41737]
- MRC [MC_UU_00007/10] Funding Source: UKRI
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.
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