Loss of tubedown expression as a contributing factor in the development of age-related retinopathy.
OBJECTIVE
Tubedown (Tbdn), a cortactin-binding acetyltransferase subunit, regulates retinal vascular permeability and homeostasis in adulthood. Here the authors explore whether Tbdn loss during aging might contribute to the mechanisms underlying age-related neovascular retinopathy.


METHODS
A conditional endothelial-specific transgenic model of Tbdn loss was compared with aged mouse and human specimens from 5- to 93-year-old individuals. Specimens were analyzed by morphometric measurements and for functional markers using immunohistochemistry and Western blot analysis.


RESULTS
An age-dependent decrease in Tbdn expression in endothelial cells of the posterior pole of the eye correlated with pathologic changes in choroidal and retinal tissues of aged mice. In humans, aged specimens without eye disease exhibited a moderate decrease in retinal and choroidal endothelial Tbdn expression compared with younger persons, whereas a greater decrease in choroid vascular Tbdn expression was observed in patients with age-related macular degeneration. In mice, Tbdn loss resulting from old age or conditional Tbdn knockdown was associated with retinal lesions showing significant extravascularly localized albumin and correlated with increased activity of senescence-associated β-galactosidase in the retinal pigment epithelium. A range of abnormalities in RPE, Bruch's membrane, and choriocapillaris observable at the ultrastructural level in Tbdn-knockdown eyes recapitulate those present in human AMD.


CONCLUSIONS
This work provides evidence that the marked decrease in the level of expression of Tbdn in the retinal and choroidal vasculature during aging contributes to the multifactorial process that leads to the development of age-related retinopathy and choroidopathy.
Gendron
Robert L
RL
Division of Basic Medical Sciences, Department of Medicine, Memorial University of Newfoundland, Newfoundland, Canada. rgendron@mun.ca
Laver
Nora V
NV
Good
William V
WV
Grossniklaus
Hans E
HE
Miskiewicz
Ewa
E
Whelan
Maria A
MA
Walker
Jacqueline
J
Paradis
Hélène
H
D000123:Acetyltransferases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology; D000818:Animals; D001485:Basement Membrane / Q000201:enzymology / Q000648:ultrastructure; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D002829:Choroid / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008268:Macular Degeneration / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D012160:Retina / Q000201:enzymology* / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000201:enzymology / Q000648:ultrastructure
C463022:NAA15 protein, human; C427761:Naa15 protein, mouse; D009419:Nerve Tissue Proteins; D000123:Acetyltransferases; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E