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Transcriptional profiling of FACS-purified striatal medium spiny neurons in early pathological phase of Huntington disease model mice

  • P1-320
  • 宮崎 晴子 / Haruko Miyazaki:1,2,3 小山 文隆 / Fumitaka Oyama:2,4 紀 嘉浩 / Yoshihiro Kino:1,2,3 黒澤 大 / Masaru Kurosawa:1,2,3 黒澤 みず樹 / Mizuki Kurosawa:2,5 下郡 智美 / Tomomi Shimogori:3 服部 信孝 / Nobutaka Hattori:6 貫名 信行 / Nobuyuki Nukina:1,2,3 
  • 1:順天堂大院・医・神経変性 / Dept Neuroscience for Neurodegenerative Disorders, Grad Sch of med Juntendo Univ, Tokyo, Japan 2:理研・脳・構造神経病理 / Lab Structural Neuropathology, RIKEN BSI, Saitama, Japan 3:理研・脳・視床発生 / Lab Molecular Mechanisms of Thalamus Development, RIKEN BSI, Saitama, Japan 4:工学院大・工・応用化学 / Dept Applied Chemistry, Kogakuin Univ, Tokyo, Japan 5:理研・脳・神経膜機能 / Lab Molecular Membrane Neuroscience, RIKEN BSI, Saitama, Japan 6:順天堂大院・医・神経学 / Dept Neurology, Grad Sch of med Juntendo Univ, Tokyo, Japan 

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in HTT which encodes the huntingtin protein. The major pathological features in HD are aggregation of mutant huntingtin proteins (mHTT) containing expanded polyglutamine (polyQ) in nucleus and selective striatal neuronal loss, mainly medium spiny neurons (MSNs). mHTT aggregation accompanies sequestration of transcriptional regulatory factors, leading to alteration of genes expression in the brain of HD patients and HD model mice, suggesting that transcriptional dysregulation is a central mechanism in HD pathogenesis. Previous studies of transcriptional profiling using DNA microarray provided great considerations to understand HD pathogenesis, although heterogeneity of mammalian nerve system limited the power of the analysis. In this study, we created transcriptome database provided from MSNs in presymptomatic HD model mouse to examine initial alterations of gene expression in MSNs. We developed DNA microarray method using fluorescent activated cell sorting (FACS) technique to highly purify MSNs. To label MSNs in HD model mouse, we established double-transgenic mice by crossing R6/2 with Scn4b promoter-driven Venus expressing transgenic mouse (Scn4b-Venus). In the striatum, Scn4b is strongly expressed in MSNs and fast downregulated in early pathological phase of R6/2. The altered genes set of Venus-positive cells from double-transgenic mice contains typically dysregulated genes in HD (e.g., Scn4b, Penk, and Drd1a), interestingly also contains dysregulated genes in late stage of R6/2 (e.g., Nfya and Cacna2d3), but excludes Gfap, which is an upregulated astrocytic gene in whole-striatum array of R6/2.

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