AMD-Associated HTRA1 Variants Do Not Influence TGF-β Signaling in Microglia.

Abstract

Genetic variants of high-temperature requirement A serine peptidase 1 (HTRA1) and age-related maculopathy susceptibility 2 (ARMS2) are associated with age-related macular degeneration (AMD). One HTRA1 single nucleotide polymorphism (SNP) is situated in the promotor region (rs11200638) resulting in increased expression, while two synonymous SNPs are located in exon 1 (rs1049331:C > T, rs2293870:G > T). HtrA1 is known to inhibit transforming growth factor-β (TGF-β) signaling, a pathway regulating quiescence of microglia, the resident immune cells of the brain and retina. Microglia-mediated immune responses contribute to AMD pathogenesis. It is currently unclear whether AMD-associated HTRA1 variants influence TGF-β signaling and microglia phenotypes. Here, we show that an HtrA1 isoform carrying AMD-associated SNPs in exon 1 exhibits increased proteolytic activity. However, when incubating TGF-β-treated reactive microglia with HtrA1 protein variants, neither the wildtype nor the SNP-associated isoforms changed microglia activation in vitro.

• Authors: Isha Akhtar-Schaefer, Raphael Reuten, Manuel Koch, Markus Pietsch, Thomas Langmann
• Journal: Advances in experimental medicine and biology (Adv Exp Med Biol) Vol. 1185 Pg. 3-7 ( 2019) ISSN: 0065-2598 [Print] United States
• PMID: 31884580 (Publication Type: Journal Article)

Chemical References

• Transforming Growth Factor beta
• High-Temperature Requirement A Serine Peptidase 1
• HtrA1 protein, human
• Serine Endopeptidases

Topics

• Genetic Predisposition to Disease
• Genotype
• High-Temperature Requirement A Serine Peptidase 1 (genetics)
• Humans
• Macular Degeneration (genetics)
• Microglia (metabolism)
• Polymorphism, Single Nucleotide
• Serine Endopeptidases
• Signal Transduction
• Transforming Growth Factor beta (metabolism)