Degeneration of neurons, synapses, and neuropil and glial activation in a murine Atm knockout model of ataxia–telangiectasia

Abstract

Neural degeneration is one of the clinical manifestations of ataxia-telangiectasia, a disorder caused by mutations in the Atm protein kinase gene. However, neural degeneration was not detected with general purpose light microscopic methods in previous studies using several different lines of mice with disrupted Atm genes. Here, we show electron microscopic evidence of degeneration of several different types of neurons in the cerebellar cortex of 2-month-old Atm knockout mice, which is accompanied by glial activation, deterioration of neuropil structure, and both pre-and postsynaptic degeneration. These findings are similar to those in patients with ataxia-telangiectasia, indicating that Atm knockout mice are a useful model to elucidate the mechanisms underlying neurodegeneration in this condition and to develop and test strategies to palliate and prevent the disease.

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

“…41,44,45 Electron microscopy observations have detected structural activation of glial cells in Atm knockout mice. 46 Ultrastructural alterations in astrocytes have been demonstrated alongside neuronal degenerative processes in Atm Ϫ/Ϫ mice in cerebellar tissue. 46 Furthermore, astrocytes from Atm Ϫ/Ϫ mice exhibited growth arrest and growth defects, which may be due to oxidative stress.…”

“…46 Ultrastructural alterations in astrocytes have been demonstrated alongside neuronal degenerative processes in Atm Ϫ/Ϫ mice in cerebellar tissue. 46 Furthermore, astrocytes from Atm Ϫ/Ϫ mice exhibited growth arrest and growth defects, which may be due to oxidative stress. 41,47 Retinal neurons are terminally differentiated and are therefore, like other neurons in the brain, irreplaceable.…”

“…These findings concur with subtle neurological abnormalities reported previously, including electrophysiological deficiencies. 15,22,46,[72][73][74][75][76][77] The symptomatic picture presented in A-T patients is complex and multifaceted, partly progressive, and occasionally fixed over a limited period of time. The diversity of systems affected by the disease and their interconnections makes it difficult to determine which of the disease manifestations is primary and which reflects added systemic complications.…”

ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes

“…It has been shown that ATM deficiency in the Atm À/À mouse brain results postnatally in deficient dendritogenesis in Purkinje neurons 9 as well as reduced cell size and diminished cell density in substantia nigral dopaminergic neurons. 8,10 Atm À/À mice also show 'predegenerative' CNS lesions with age-dependent neuronal cell loss and gliosis, 11 dystrophic Purkinje cells, 12 and indicators of Purkinje cell cycle re-entry postnatally. 13 It has also been reported that in vitro survival of cerebellar Purkinje cells from Atm À/À mice is significantly reduced compared with their wild-type littermates.…”

SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs

“…However, the tested cells were not the most relevant cell targets for A-T treatment, as cerebellar neural cells are thought to be the primary targets for abrogating neurodegeneration in patients. Furthermore, Atm knockout (Atm À / À ) mice do not manifest the progressive ataxia seen in A-T patients and also fail to show marked loss of Purkinje cells (PCs) in the cerebellum, currently believed to be a hallmark of the ATM-related neural deficits observed in disease [16][17][18] .…”