<scp>HTRA</scp>1, an age‐related macular degeneration protease, processes extracellular matrix proteins <scp>EFEMP</scp>1 and <scp>TSP</scp>1

Lin, Michael K.; Yang, Jin; Hsu, Chun Wei; Gore, Anuradha; Bassuk, Alexander G.; Brown, Lewis M.; Colligan, Ryan M.; Sengillo, Jesse D.; Mahajan, Vinit B.; Tsang, Stephen H.

doi:10.1111/acel.12710

Cited by 79 publications

(69 citation statements)

References 27 publications

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“…Thus, the higher RGR expression in the foveal MGs might meet the high demand of cone visual pigment regeneration in the cone-dominated fovea. Additionally, HTRA1, a risk factor gene of AMD, exhibited high expression in the fovea MGs, consistent with the fovea being more vulnerable in AMD [37,38]. Together, our results indicated that MGs in the fovea, as a type of supporting glial cell, expressed specific genes for facilitating cone photoreceptor regeneration, specification, and functional maintenance.…”

Section: Regionally Different Transcriptomes Of Primate Mgs and Conessupporting

confidence: 79%

“…We collected single-cell transcriptomic profiles of 119,520 cells, including 38,558 from six healthy human samples (one 8-day old infant and, five adults aged between 35 and 87 years old) and 80,962 from five macaque samples (one 2-year old juvenile and four adults aged between 4 and 23 years old) ( Supplementary Table 1), which covered progressive retinal aging, using dropletbased scRNA-seq (10x Genomics platform). Retinae were dissociated from 1.5-2.0 mm and 5 mm diameter pieces around the center of the foveal pit to represent foveal and peripheral cells, respectively ( Fig.…”

Section: Single-cell Transcriptomes Of Primate Retinamentioning

confidence: 99%

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A single-cell transcriptome atlas of the aging human and macaque retina

Lü

Zhong

et al. 2020

Preprint

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The human retina is a complex neural tissue that detects light and sends visual information to the brain. However, the molecular and cellular processes that underlie aging primate retina remain unclear. Here, we provide a comprehensive transcriptomic atlas based on 119,520 single cells of the foveal and peripheral retina of humans and macaques covering different ages. The molecular features of retinal cells differed between the two species, suggesting the distinct regional and species specializations of the human and macaque retinae. In addition, human retinal aging occurred in a region- and cell-type- specific manner. Aging of human retina exhibited a foveal to peripheral gradient. MYO9A- rods and a horizontal cell subtype were greatly reduced in aging retina, indicating their vulnerability to aging. Moreover, we generated a dataset showing the cell-type- and region- specific gene expression associated with 55 types of human retinal disease, which provides a foundation to understand the molecular and cellular mechanisms underlying human retinal diseases. Together, these datasets are valuable for understanding the molecular characteristics of primate retina, as well as the molecular regulation of aging progression and related diseases.

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Section: Regionally Different Transcriptomes Of Primate Mgs and Conessupporting

confidence: 79%

Section: Single-cell Transcriptomes Of Primate Retinamentioning

confidence: 99%

A single-cell transcriptome atlas of the aging human and macaque retina

Lü

Zhong

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Recent studies show that a promoter variant causing increased expression of HTRA1 in RPE cells leads to elevated levels of ECM proteins including HTRA1 substrates (Lin et al, ). Specifically, the HTRA1 substrates vitronectin, clusterin, Adam9, C3, and tubulin were also detected in the human RPE secretome (An et al, ; Melo et al, ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2019

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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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“…Also, HtrA1 has been suggested to play a critical role in angiogenesis via TGF-β signalling [37]. Recently, HtrA1 was reported to processes extracellular matrix proteins such as thrombospondin 1 in inducing AMD [38]. It is likely that these HtrA1 actions contribute to the disruption of endothelial tube formation, future studies are warranted to investigate the molecular mechanisms of HtrA1 action in inducing endothelial dysfunction, which will provide important insights into the understanding of how elevated levels of HtrA1 contribute to AMD and earlyonset PE.…”

Section: Resultsmentioning

confidence: 99%

HtrA1 alters endothelial tube formation characteristics in an in vitro model

Singh

Nie

2019

Preprint

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High temperature requirement factor A1 (HtrA1) is a serine protease of the mammalian HtrA family. It is ubiquitously expressed with high levels in the placenta. Dysregulation of HtrA1 has been linked to a number of diseases, in particular age-related macular degeneration (AMD) and preeclampsia (PE) in which HtrA1 is significantly increased.AMD is the leading cause of irreversible visual impairment in older people, affecting millions across the globe. PE is a life-threatening pregnancy complication, affecting 2-7% of pregnant women worldwide. Although AMD and PE are very different diseases, both are associated with endothelial dysfunction and dysregulation of angiogenesis.Given HtrA1 is up-regulated in both AMD and PE, in this study we examined the impact of excessive HtrA1 on capillary tube formation of HUVECs as an in vitro angiogenesis model. HtrA1 at high concentrations significantly increased the total number of tube branch points and inter-tubular loops, but considerably decreased the mean tube length, resulting in more but much smaller tubes. However, these smaller tubes were incomplete/broken. These data demonstrated that high concentrations of HtrA1 altered endothelial tube formation characteristics of HUVEVs. Our results suggest that HtrA1 over-expression in AMD and PE may directly contribute to the endothelial dysfunction in these diseases.

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HTRA1, an age‐related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1

Cited by 79 publications

References 27 publications

A single-cell transcriptome atlas of the aging human and macaque retina

A single-cell transcriptome atlas of the aging human and macaque retina

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

HtrA1 alters endothelial tube formation characteristics in an in vitro model

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