title: 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.
authors.affiliation: Department of Neurobiology, George S. Wise, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Galron
authors.forename: Ralph
authors.initials: R
authors.lastname: Gruber
authors.forename: Veronica
authors.initials: V
authors.lastname: Lifshitz
authors.forename: Haizhen
authors.initials: H
authors.lastname: Lu
authors.forename: Michal
authors.initials: M
authors.lastname: Kirshner
authors.forename: Natali
authors.initials: N
authors.lastname: Ziv
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shiloh
authors.forename: Ari
authors.initials: A
authors.lastname: Barzilai
authors.forename: Dan
authors.initials: D
authors.lastname: Frenkel
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000473:pathology*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D049932:Nijmegen Breakage Syndrome / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins