Astrocyte Dysfunction Associated with Cerebellar Attrition in a Nijmegen Breakage Syndrome Animal Model

Abstract

Nijmegen breakage syndrome (NBS) is a genomic instability disorder caused by hypomorphic mutations in the Nbs1 gene. When Nbs1 is conditionally inactivated in the central nervous system of mice (Nbs1-CNS-Δ), they suffer from severe cerebellar atrophy, ataxia, and white matter damage. Here, we show that conditional inactivation of the murine Nbs1 gene has a profound effect on the integrity and the functionality of the glial cells, which suggests their crucial role in the pathogenesis of NBS. Interestingly, in Nbs1-CNS-Δ mice, the dramatic reduction in the numbers of Purkinje and granule cells was also linked to a reduction of microglial cells but not to astrocytes (GFAP+), suggesting an impairment in astrocytic functionality. Nbs1 levels were dramatically reduced in adult astrocyte isolated from Nbs1-CNS-Δ mice, suggesting a major role in cerebellar pathology. In order to investigate the effect of Nbs1 deletion on astrocyte activity, we investigated glutamine synthetase levels in astrocyte and discovered 40% reduction as compared to WT. Furthermore, we found a significant reduction in the secretion of neurotrophic factors, such as brain-derived neurotrophic factor and neurotrophin 3. Understanding the contribution of malfunctioning astrocytes to the etiology of NBS can elucidate a hitherto unknown aspect of this disorder.

DNA damage and oxidative injury are associated with hypomyelination in the corpus callosum of newborn NbnCNS‐del mice

“…The current study shows that Nbn gene inactivation contributes to white matter neurodegeneration, optic nerve impairment (Assaf et al, 2008), and cataractogenesis (Yang et al, 2006). In addition, Nbn gene inactivation also disrupts the functional integrity of glial cells in the developing cerebellum, reducing the neurotrophic-protection role in neuronal cell growth (Galron et al, 2011).…”

A distinct response to endogenous DNA damage in the development of Nbs1-deficient cortical neurons

“…The most striking phenotype of these mice is an early postnatal ataxia caused by the agenesis of the cerebellum with decreased proliferation in neuronal progenitors, and massive cell death in cerebellar neuronal cells 18 . In addition, Nbn CNS-del mice displayed microcephaly and severely affected white matter integrity, retina and astrocyte functionality 19, 20, 21 . However, the nature of cerebral reduction and the underlying molecular mechanism in Nbn CNS-del mice have not been investigated.…”

Malfunctioning DNA Damage Response (DDR) Leads to the Degeneration of Nigro-Striatal Pathway in Mouse Brain

“…However, Atm-deficient mice display very mild cerebellar defects but exhibit severe age-dependent degeneration of tyrosine hydroxylase-positive, dopaminergic nigro-striatal neurons (Eilam et al 1998(Eilam et al , 2003. In contrast, specific inactivation of the Nbs1 gene in the CNS caused marked cerebral, cerebellar, and retinal attrition in the Nbs1-CNS-Δ mice (Frappart et al 2005;Assaf et al 2008;Baranes et al 2009;Galron et al 2011). The fact that Nbs1, which is an exclusive component of the DDR machinery and one of the Atm activators (Uziel et al 2003;Falck et al 2005;Dar et al 2011) plays such an essential role in CNS homeostasis can serve as a good model system to test our hypothesis that malfunctioning DDR is indeed the major contributor to CNS degeneration observed in genomic instability disorders.…”