TY - JOUR
T1 - A role for vascular deficiency in retinal pathology in a mouse model of ataxia-telangiectasia
AU - Raz-Prag, Dorit
AU - Galron, Ronit
AU - Segev-Amzaleg, Niva
AU - Solomon, Arieh S.
AU - Shiloh, Yosef
AU - Barzilai, Ari
AU - Frenkel, Dan
N1 - Funding Information:
Supported by grants from the Human Frontier Science Program organization: CDA – 0019/2008-C; and Legacy Heritage Biomedical Science Partnership: 862/09. Work in the laboratory of A.B. was supported by research grants from the A-T Children's Project : 160240 ; the Israeli Ministry of Health: 3-00000-6068; Israel Science Foundation: 365/08; US-Israel Binational Science Foundation: 2005046; and the German-Israeli Foundation (GIF): I-935-270.1/2006. Work in the laboratory of Y.S. was supported by the A-T Medical Research Foundation, the A-T Ease Foundation, and the Israel Cancer Research Fund. Y.S. is a Research Professor of the Israel Cancer Research Fund.
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052847814&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2011.05.026
DO - 10.1016/j.ajpath.2011.05.026
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C2 - 21763675
AN - SCOPUS:80052847814
SN - 0002-9440
VL - 179
SP - 1533
EP - 1541
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -