A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

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 Atmdeficient 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. Some brain disorders may have a vascular origin, 1,2 and vascular diseases can be directly linked to neuronal and synaptic dysfunction through changes in the blood flow, increase in blood-brain barrier permeability, and in nutrient supply. 3 A healthy brain relies on the proper function and communication of all cells comprising the neurovascular unit: neurons, astrocytes, brain endothelium, and vascular smooth muscle cells. 4 Impaired genomic stability interferes with cellular homeostasis and poses a constant threat to cellular viability. 5 The cell combats this threat by activating the DNA damage response (DDR), a complex signaling network that detects the DNA lesions, promotes their repair, and temporarily modulates cellular metabolism while the damage is being repaired. 6 The DDR is vigorously activated by DNA double-strand breaks (DSBs), a particularly cytotoxic DNA lesion induced by ionizing radiation, radiomimetic chemicals, and oxygen radicals. 7,8 The DNA damage response is a hierarchical process executed by sensor/mediator proteins that accumulate at DSB sites and by protein kinases that serve as transducers of the DNA damage alarm to numerous downstream effectors. 6 The primary transducer of the cellular response to DSBs is the protein kinase ATM, which phosphorylates many key players in the various branches of the DDR. 9 Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene that encodes the ATM protein. 10 A-T is characterized by progressive neurodegeneration affecting mainly the cerebellum, which develops into severe neuromotor dysfunction;

Cerebral Abnormalities in Adults with Ataxia-Telangiectasia

“…The ocular and cutaneous telangiectasias that are part of the defining feature of A-T appear in light-exposed superficial regions. A similar vascular pathologic pattern in ATM-deficient mice 21 that arises in the retina with diminished retinal vasculature attenuation is associated with increased vascular endothelial growth factor expression (implicated in angiogenesis), decreased tight junction protein occludin expression, and perturbed astrocytic interaction with endothelial cells, as well as increased vascular permeability with deposits of hemosiderin; however, this model differs from the deep brain lesions demonstrated in this case series by its relationship to light exposure. 22 Another plausible explanation is offered by growing evidence that ATM mediates vascular endothelial cell senescence.…”

Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage

“…4A-D). Telangiectasia are one of the cardinal features of A-T [3], and increased vascular permeability and activation of glial cells were reported in the retina of Atm 2/2 mice [48]. Likewise, there was increased glial cell activation in the retina of sick Atm LP/LP animals, as well as Atm 2/2 rats [unpublished results] (Supplemental Fig.…”

“…DNA-damaging agents [48,72]. A knock-in mouse model expressing a mutant form of Atm, corresponding to a common patient mutation [7636del9, resulting in the loss of 3 amino acid residues (serine, arginine, isoleucine; 2556-2558)], had a significantly longer lifespan than Atm 2/2 mice when maintained under nonspecific, pathogen-free conditions, which could be accounted for by a lower incidence of thymic lymphomas and extensive apoptosis in these lymphomas [73].…”

Astrocytes restore connectivity and synchronization in dysfunctional cerebellar networks

“…Previous studies showed that astrocyte coverage of blood vessels is dramatically reduced in the retinas of Atm −/− mice (10). We performed immunostaining to determine whether astrocyte complexity was also altered in Atm −/− cerebellar cultures.…”

“…The gene encoding ATM is mutated in the human genetic disease ataxia-telangiectasia (A-T) (8,9). One of the most devastating symptoms of A-T is the cerebellar ataxia, with significant loss of Purkinje and granule neurons in the cerebellum, that leads progressively to general motor dysfunction (10).…”