| First Author | Chekuri A | Year | 2019 |
| Journal | Aging Cell | Volume | 18 |
| Issue | 6 | Pages | e13011 |
| PubMed ID | 31385385 | Mgi Jnum | J:280066 |
| Mgi Id | MGI:6367882 | Doi | 10.1111/acel.13011 |
| Citation | Chekuri A, et al. (2019) Late-onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1. Aging Cell :e13011 |
| abstractText | 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. |
