A role for vascular deficiency in retinal pathology in a mouse model of ataxia-telangiectasia

Dorit Raz-Prag, Ronit Galron, Niva Segev-Amzaleg, Arieh S. Solomon, Yosef Shiloh, Ari Barzilai, Dan Frenkel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Ataxia-telangiectasia is a multifaceted syndrome caused by null mutations in the ATM gene, which encodes the protein kinase ATM, a key participant in the DNA damage response. Retinal neurons are highly susceptible to DNA damage because they are terminally differentiated and have the highest metabolic activity in the central nervous system. In this study, we characterized the retina in young and aged Atm-deficient mice (Atm -/-). At 2 months of age, angiography revealed faint retinal vasculature in Atm -/- animals relative to wild-type controls. This finding was accompanied by increased expression of vascular endothelial growth factor protein and mRNA. Fibrinogen, generally absent from wild-type retinal tissue, was evident in Atm -/- retinas, whereas mRNA of the tight junction protein occludin was significantly decreased. Immunohistochemistry labeling for occludin in 6-month-old mice showed that this decrease persists in advanced stages of the disease. Concurrently, we noticed vascular leakage in Atm -/- retinas. Labeling for glial fibrillary acidic protein demonstrated morphological alterations in glial cells in Atm -/- retinas. Electroretinographic examination revealed amplitude aberrations in 2-month-old Atm -/- mice, which progressed to significant functional deficits in the older mice. These results suggest that impaired vascularization and astrocyteendothelial cell interactions in the central nervous system play an important role in the etiology of ataxia-telangiectasia and that vascular abnormalities may underlie or aggravate neurodegeneration.

Original languageEnglish
Pages (from-to)1533-1541
Number of pages9
JournalAmerican Journal of Pathology
Volume179
Issue number3
DOIs
StatePublished - Sep 2011

Funding

FundersFunder number
Human Frontier Science Program862/09, 160240
Israel Science Foundation365/08
Israel Cancer Research Fund
Medical Research Foundation
United States-Israel Binational Science Foundation2005046
Ministry of Health, State of Israel3-00000-6068
A-T Ease Foundation
German-Israeli Foundation for Scientific Research and DevelopmentI-935-270.1/2006

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