PUBLICATION

High Temperature Requirement A 1 (HTRA1) Causes Photoreceptor Cell Death in Zebrafish Disease Models

Authors
Oura, Y., Nakamura, M., Takigawa, T., Fukushima, Y., Wakabayashi, T., Tsujikawa, M., Nishida, K.
ID
ZDB-PUB-181003-11
Date
2018
Source
The American journal of pathology   188(12): 2729-2744 (Journal)
Registered Authors
Tsujikawa, Motokazu
Keywords
none
MeSH Terms
  • Aged
  • Animals
  • Animals, Genetically Modified
  • Apoptosis
  • Cells, Cultured
  • Disease Models, Animal*
  • Female
  • High-Temperature Requirement A Serine Peptidase 1/genetics
  • High-Temperature Requirement A Serine Peptidase 1/metabolism*
  • Humans
  • Macular Degeneration/metabolism
  • Macular Degeneration/pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Photoreceptor Cells/metabolism
  • Photoreceptor Cells/pathology*
  • Retinal Pigment Epithelium/metabolism
  • Retinal Pigment Epithelium/pathology*
  • Signal Transduction
  • Zebrafish
PubMed
30273602 Full text @ Am. J. Pathol.
Abstract
Age-related macular degeneration (AMD) is an important cause of blindness. It is characterized by a retinal pigment epithelium (RPE) disorder that leads to death of photoreceptor cells (PRCs). AMD has a strong genetic association with high temperature requirement A 1 (HTRA1). The relationship between HTRA1 and the AMD phenotype is unknown. In this study, we show that the expression of HTRA1 in PRCs, as well as in RPE, is increased by the disease-associated HTRA1 mutation and aging. TUNEL assay and quantitative PCR of apoptosis-associated caspases confirmed that PRC-specific overexpression of HTRA1 induced PRC death. Transgenic zebrafish overexpressing human HTRA1 in rod PRCs showed morphological changes of the RPE, including PRC death and lipofuscin accumulation, features similar to those of early AMD. htra1 expression was also increased in a retinitis pigmentosa zebrafish model compared with wild-type. In both fish lines, PRC death was rescued by the suppression of htra1 by the inhibitor 6-boroV. AKT-FOXO3 signaling downstream of HTRA1 was activated via a tumor growth factor β signal, resulting in PRC death. These findings suggest that HTRA1 derived from PRCs is associated with early AMD via PRC death. HTRA1 is a potentially effective target for neuroprotective therapy of early AMD and other degenerative diseases of PRCs.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes