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Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model.

ABSTRACT: Severe hyperbilirubinemia is toxic during central nervous system development. Prolonged and uncontrolled high levels of unconjugated bilirubin lead to bilirubin-induced neurological damage and eventually death by kernicterus. Bilirubin neurotoxicity is characterized by a wide array of neurological deficits, including irreversible abnormalities in motor, sensitive and cognitive functions, due to bilirubin accumulation in the brain. Despite the abundant literature documenting the in vitro and in vivo toxic effects of bilirubin, it is unclear which molecular and cellular events actually characterize bilirubin-induced neurodegeneration in vivo.We used a mouse model of neonatal hyperbilirubinemia to temporally and spatially define the response of the developing cerebellum to the bilirubin insult.We showed that the exposure of developing cerebellum to sustained bilirubin levels induces the activation of oxidative stress, ER stress and inflammatory markers at the early stages of the disease onset. In particular, we identified TNF? and NFK? as key mediators of bilirubin-induced inflammatory response. Moreover, we reported that M1 type microglia is increasingly activated during disease progression. Failure to counteract this overwhelming stress condition resulted in the induction of the apoptotic pathway and the generation of the glial scar. Finally, bilirubin induced the autophagy pathway in the stages preceding death of the animals.This study demonstrates that inflammation is a key contributor to bilirubin damage that cooperates with ER stress in the onset of neurotoxicity. Pharmacological modulation of the inflammatory pathway may be a potential intervention target to ameliorate neonatal lethality in Ugt1 -/- mice.

SUBMITTER: Vodret S

PROVIDER: S-EPMC5366125 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 <sup>-/-</sup> mouse model.

Vodret Simone S Bortolussi Giulia G Jašprová Jana J Vitek Libor L Muro Andrés F AF

Journal of neuroinflammation 20170324 1

<h4>Background</h4>Severe hyperbilirubinemia is toxic during central nervous system development. Prolonged and uncontrolled high levels of unconjugated bilirubin lead to bilirubin-induced neurological damage and eventually death by kernicterus. Bilirubin neurotoxicity is characterized by a wide array of neurological deficits, including irreversible abnormalities in motor, sensitive and cognitive functions, due to bilirubin accumulation in the brain. Despite the abundant literature documenting th ...[more]

PMID: 28340583

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Project description:Neonatal hyperbilirubinemia (jaundice) is common in infants, with extremely preterm infants (EPT, <28 weeks gestational age) being at high risk for bilirubin-induced neurotoxicity, resulting in neurodevelopmental impairment. Hyperbilirubinemia is treated using phototherapy to lower unconjugated bilirubin levels. However, the benefits and risks of phototherapy in EPTs have not been well studied, and bilirubin at low levels may be protective as an antioxidant. Phototherapy is associated with markers of oxidative stress in the plasma, but the effects of phototherapy on the hippocampus (HPC) are not known. Bilirubin and insults associated with EPTs impair hippocampal development, a brain structure critical for cognitive function, but their underlying mechanisms remain unknown. The effects of hyperbilirubinemia and phototherapy on the HPC were studied using a Gunn rat model. Jaundiced (jj) and non-jaundiced (Nj) pups were subjected to phototherapy from postnatal day 4 (P4) through P6. The HPC was harvested and processed for RNA sequencing. Serum bilirubin levels were elevated in jj compared to Nj control rats. Phototherapy significantly lowered serum bilirubin levels in jj rats. Compared to Nj rats, 1294 genes were differentially expressed in the jj hippocampal transcriptome and mapped onto the nervous system development, inflammation, and ferroptosis signaling pathways. Phototherapy induces 3297 differentially-expressed genes (DEGs) in rat hippocampal transcriptome compared to untreated rats. These DEGs were annotated to pathways regulating synaptogenesis, long-term potentiation, and neurogenesis. Both hyperbilirubinemia and phototherapy altered expression of 407 genes, which mapped onto hippocampal plasticity functions, including neuritogenesis and long-term potentiation. Our study demonstrates a model for investigating molecular effects of hyperbilirubemia and phototherapy in an EPT-equivalent Gunn rat pup. Our data revealed the effects of hyperbilirubinemia and phototherapy on signaling pathways critical for hippocampal development and plasticity.

Project description:BACKGROUND: Down syndrome is a chromosomal disorder caused by the presence of three copies of chromosome 21. The mechanisms by which this aneuploidy produces the complex and variable phenotype observed in people with Down syndrome are still under discussion. Recent studies have demonstrated an increased transcript level of the three-copy genes with some dosage compensation or amplification for a subset of them. The impact of this gene dosage effect on the whole transcriptome is still debated and longitudinal studies assessing the variability among samples, tissues and developmental stages are needed. RESULTS: We thus designed a large scale gene expression study in mice (the Ts1Cje Down syndrome mouse model) in which we could measure the effects of trisomy 21 on a large number of samples (74 in total) in a tissue that is affected in Down syndrome (the cerebellum) and where we could quantify the defect during postnatal development in order to correlate gene expression changes to the phenotype observed. Statistical analysis of microarray data revealed a major gene dosage effect: for the three-copy genes as well as for a 2 Mb segment from mouse chromosome 12 that we show for the first time as being deleted in the Ts1Cje mice. This gene dosage effect impacts moderately on the expression of euploid genes (2.4 to 7.5% differentially expressed). Only 13 genes were significantly dysregulated in Ts1Cje mice at all four postnatal development stages studied from birth to 10 days after birth, and among them are 6 three-copy genes. The decrease in granule cell proliferation demonstrated in newborn Ts1Cje cerebellum was correlated with a major gene dosage effect on the transcriptome in dissected cerebellar external granule cell layer. CONCLUSION: High throughput gene expression analysis in the cerebellum of a large number of samples of Ts1Cje and euploid mice has revealed a prevailing gene dosage effect on triplicated genes. Moreover using an enriched cell population that is thought responsible for the cerebellar hypoplasia in Down syndrome, a global destabilization of gene expression was not detected. Altogether these results strongly suggest that the three-copy genes are directly responsible for the phenotype present in cerebellum. We provide here a short list of candidate genes.

Dataset Information

Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model.

Publications

Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 <sup>-/-</sup> mouse model.

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