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Neuroprotection, Neurotoxicity and Neuroinflammation

開催日 2014/9/11
時間 16:00 - 17:00
会場 Poster / Exhibition(Event Hall B)

転写因子Nrf1 (NFE2L1) による神経細胞の恒常性維持機構の解析
Homeostatic maintenance of neuronal activity by the transcription factor Nrf1 (NFE2L1)

  • P1-342
  • 岡室 翔太 / Shota Okamuro:1 谷口 浩章 / Hiroaki Taniguchi:1 金澤 唯 / Yui Kanazawa:1 小林 聡  / Akira Kobayashi:1 
  • 1:同志社大院・生命医科・遺伝情報 / Lab. for Genetic Code, Grad. Sch. of Life & Med. Sci., Doshisha Univ., Kyoto, Japan 

The central nervous system (CNS) - specific Nrf1 knockout (KO) mice show progressive motor ataxia with accumulation of ubiquitinated proteins and die within 3 weeks. From these phenotypes, it is assumed that Nrf1 maintains the CNS homeostasis. However, the precise mechanism of Nrf1 function is not clear. Thus, the purpose of this study is to identify genes associated with neurodegeneration found in CNS-specific Nrf1 KO mice. We further performed pathological analysis of the neurodegeneration in the mice.

To identify Nrf1 mRNA expression in the brain, we first performed in situ hybridization using brain sections from wild-type mice at postnatal day 7 (P7) and P14. We found the Nrf1 mRNA expression primarily in Purkinje cells, cerebellar nuclei, hypothalamus, hippocampus, cerebral cortex and olfactory bulb. In support of this result, Nrf1 deletion in these neural tissues caused aberrant accumulation of polyubiquitinated proteins. Next we examined the expression level of proteasome subunit genes as Nrf1 target genes in the cerebellum of KO mice by realtime-PCR. However, we could not find any alternation when compared with control mice. Interestingly, expression of prosurvival transcription factor MEF2A and MEF2C at P7 was increased in Nrf1 deficient cerebellum. Immunofluorescent staining of calbindin, which is Purkinje cell-specific marker, revealed no abnormalities in the form and arrangement of Nrf1-deficient Purkinje cells. Finally, we identified atrophy of the liver and the spleen in P18 KO mice, suggesting that this phenotype is involved in the lethality of KO mice.

Taken together, these results suggest that neurodegeneration accompanied with polyubiquitinated protein accumulation is not due to reduced expression of proteasome genes in KO mice. We are currently working on identifying Nrf1 downstream genes related to neural homeostasis using microarray analysis.

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