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

  • Author(s): Chekuri, Anil
  • Zientara-Rytter, Katarzyna
  • Soto-Hermida, Angel
  • Borooah, Shyamanga
  • Voronchikhina, Marina
  • Biswas, Pooja
  • Kumar, Virender
  • Goodsell, David
  • Hayward, Caroline
  • Shaw, Peter
  • Stanton, Chloe
  • Garland, Donita
  • Subramani, Suresh
  • Ayyagari, Radha
  • et al.

Published Web Location

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826137/
No data is associated with this publication.
Abstract

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 (Ctrp5S163R/wt ), and homozygous knock-in (Ctrp5S163R/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 Ctrp5S163R/S163R and Ctrp5S163R/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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