Pathological roles of sodium channel β4 subunit in Huntington disease transgenic mice

钠通道β4亚基在亨廷顿病转基因小鼠中的病理作用

• 批准号: 18500284
• 负责人: OYAMA Fumitaka
• 金额: $ 2.63万
• 依托单位: The Institute of Physical and Chemical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18500284/
• 关键词: 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

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.

钠通道β4（Sodium channelβ4，β4）是新近发现的电压门控钠通道的辅助亚基，亨廷顿病（Huntington disease，HD）是一种常染色体显性遗传的神经退行性疾病，以舞蹈病、精神障碍和痴呆为特征。HD是由亨廷顿蛋白（一种350 kDa的细胞质蛋白）氨基末端的多聚谷氨酰胺（polyQ）扩增引起的。为了找到HD发病机制中主要受影响的基因，我们使用高密度寡核苷酸阵列分析了HD转基因小鼠，并将P4鉴定为在HD模型小鼠和患者纹状体中显著下调的EST。β4亚基的减少开始于HD模型小鼠的症状前阶段，而其他电压门控离子通道亚基的减少较晚。相比之下，脊髓神经元仅产生可忽略水平的扩增聚谷氨酰胺聚集体，即使在症状阶段也维持正常水平的β4表达。β4在Neuro 2a细胞中的过表达促进了神经突延伸，并增加了富含F-actin的丝状伪足样突起的数量，表明134调节神经突生长活性。最近，我们发现β4是β位点APP裂解酶（BACE 1）的一种新底物，BACE 1是一种膜结合的乙酰化蛋白酶，可裂解淀粉样前体蛋白（APP）。而BACE 1与β4的共表达进一步加速了神经突的延伸，减少了丝状伪足样突起的数量。此外，β4在海马原代神经元中的过表达引起神经元中树突的增厚和树突棘的密度增加。提示β4下调可能导致HD转基因小鼠和HD患者纹状体钠通道异常和神经突变性。

项目成果

BACE1 modulates filopodia-like protrusions induced by sodium channel β4 subunit

• DOI: 10.1016/j.bbrc.2007.06.170
• 发表时间: 2007-09-14
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Miyazaki, Haruko;Oyama, Fumitaka;Nukina, Nobuyuki
• 通讯作者: Nukina, Nobuyuki

BACE1によるナトリウムチャネルβ4サブユニットの神経突起伸長活性の制御

BACE1 对钠通道 β4 亚基神经突生长活性的调节

• 发表时间: 2007
• 作者: 宮崎 晴子;他
• 通讯作者: 他

BACE1 cleavage mediates neurite morphology induced by sodium channel β4 subunit.

BACE1 裂解通过钠通道 β4 亚基介导神经突诱导的形态。

• 发表时间: 2007
• 作者: 宮崎晴子;小山文隆;Hon-Kit Wong;金子貢巳;櫻井隆;玉岡晃;貫名信行
• 通讯作者: 貫名信行

Sodium channel beta4 subunit: down-regulation and possible involvement in neuritic degeneration in Huntington's disease transgenic mice.

钠通道β4亚基：下调并可能参与亨廷顿病转基因小鼠的神经炎变性。

• 发表时间: 2006
• 期刊: J. Neurochem. 98
• 作者: Oyama;F.;Miyazaki;H.;Sakamoto;N.;Becquet;C.;Machida;Y.;Kaneko;K.;Uchikawa;C.;Suzuki;T.;Kurosawa;M.;Ikeda;T.;Tamaoka;A.;Sakurai;T.;Nukina;N.
• 通讯作者: N.

ハンチントン病モデルマウスにおけるナトリウムチャネルβ4サブユニットの発現抑制

亨廷顿病模型小鼠钠通道β4亚基表达的抑制

• 发表时间: 2007
• 作者: 小山 文隆;他
• 通讯作者: 他