| Project/Area Number |
18500284
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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 | The Institute of Physical and Chemical Research |
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Principal Investigator |
OYAMA Fumitaka The Institute of Physical and Chemical Research, Brain Science Institute Laboratory for Structural Neuropathology, Research Scientist (40194641)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,110,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Huntington disease / Sodium channel β4 subunit / Neurodegenerative disorder / Polyglutamine expansion / Oligonucleotide array / Transgenic mouse / BACE1 / Neuritic degeneration / 病態形成における役割 / ナトリウムチャネルβ4 / 線条体 / トランスジェニックマウ / 投射ニューロン / 発現抑制 |
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| Research Abstract |
Sodium channelβ4 (β4) is a very recently identified auxiliary subunit of the voltage gated-sodium channels Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, psychiatric disturbances and dementia. HD is caused by a polyglutamine (polyQ) expansion in the amino terminus of huntingtin, a 350 kDa cytoplasmic protein. To find primarily affected gene in HD pathogenesis, we profiled HD transgenic mice using a high-density oligonucleotide array and identified P4 as an EST that was significantly downregulated in the striatum of HD model mice and patients. Reduction ofβ4 started at a presymptomatic stage of the HD model mice, whereas other voltage-gated ion channels subunits were decreased later. In contrast, spinal cord neurons, which generate only negligible levels of expanded polyglutamine aggregates, maintained normal levels of β4 expression even at the symptomatic stage. Overexpression of β4 in Neuro2a cells promoted neurite extension and increased the number of F-actin rich filopodia-like protrusions, indicating that 134 modulates neurite outgrowth activities. Recently we identified β4 as a new substrate for β-site APP cleaving enzyme (BACE1), a membrane-bound aspartyl protease that cleaves amyloid precursor protein (APP). While coexpression of BACE1 together with β4 further accelerated neurite extension, the number of filopodia-like protrusions was reduced. Furthermore, overexpression of β4 in hippocampal primary neurons caused a thickening of dendrites and increased density of dendritic spines in the neurons. These results suggest that downregulation in β4 may lead to abnormalities of sodium channel and neurite degeneration in the striatum of HD transgenic mice and HD patients.
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