| Project/Area Number |
17500231
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Yamaguchi University |
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Principal Investigator |
SHINODA Koh Yamaguchi University, Graduate School of Medicine, Department of Neuroscience, Professor (40192108)
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| Co-Investigator(Kenkyū-buntansha) |
YANAI Akie Yamaguchi University, Graduate School of Medicine, Department of Neuroscience, Assistant Professor (20284854)
FUJINAGA Ryutaro Yamaguchi University, Graduate School of Medicine, Department of Neuroscience, Assistant Professor (30335723)
KOKUBU Keiji Yamaguchi University, Graduate School of Medicine, Department of Neuroscience, Assistant Professor (00432740)
河野 純 鹿児島大学, 大学院・医歯学総合研究科, 助手 (80251924)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥2,910,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | stigmoid body / hPAX-P2 / HAP1 / spinal and bulbar muscular atrophy / Huntington's disease / androgen receptor / endoplasmic reticulum / neurocytoplasmic inclusion / sortilin / SorLA / LR11 / tublin / dynactin / エストロゲン受容体 / mRNA / 神経細胞 / 視床下部 / 脊髄球筋萎縮症 / ポリグルタミン / HAP1mRNA / 電顕法 / in situ hybridization / 免疫組織化学 |
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| Research Abstract |
The stigmoid body (STB), which was a distinct non-membrane-bound neurocytoplasmic inclusion originally detected by immunohistochemistry for human placental antigen X-P2S (hPAX-P2S), also contains huntingtin-associated protein 1 (HAP1A/B), and the HAP1A-cDNA transfection induces STB-like inclusions in cultured cells. A striking number of the STBs are preferentially distributed in the limbic and hypothalamic regions, where neurodegeneration rarely occurs, rather than the targets of neurodegeneration including the striatum, thalamus and neocortex. The current research first provided clear evidence that HAP1 interacts with androgen receptor (AR) derived from spinal-and-bulbar-muscular-atrophy (SBMA) via its ligand-binding domain in a polyQ-length-dependent manner and forms prominent inclusions sequestering polyQ-AR, and that addition of dihydrotestosterone reduces the association strength of HAP1 with ARQ25 more dramatically than that with ARQ65. Furthermore, SBMA-mutant-ARQ65-induced apop
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tosis was suppressed by cotransfection with HAP1, supporting "the HAP1/STB protection hypothesis" that the HAP1/STB plays a protective role against neurodegeneration.
In addition, the anti-hPAX-P2S antiserum was first demonstrated to recognize HAPI^<474-577> (XP2S domain) near C-terminuses of HAP1A/B in Western blotting, and hPAX-P2S-immunoreactions of the brain STB and HAP1A-induced inclusions were shown to be eliminated by pre-adsorption with HAP1^<474-577>. These findings clearly indicated that hPAX-P2S is identical with STB-constituted HAP1 and that the HAP1-induced/immunoreactive inclusions correspond to the hPAX-P2S-immunoreactive STBs. In addition, the anti-hPAX-P2S antiserum far weakly immunostained HAP1B-induced/immunoreactive diffuse structures, suggesting that the XP2S domain is covered by some molecule in the diffuse structures and disclosed in the STB and have an important clue to elucidate mechanism of the STB formation. In immuno-electron microscopy, HAP1 is not only localized to the STB but also associated with endoplasmic-reticulum-like tubular structures adjacent to the STB, but the STB is not detected so far by any antibodies to organelle-markers including KDEL, GMP130, LAMP1, EEA1 or Bcl2. The organelle origin has yet to be determined. Less
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