Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease
Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease
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DOI：
10.1523/jneurosci.1197-04.2004
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发表时间：
2004-09-01
影响因子：
5.3
通讯作者：
Alberch, J
中科院分区：
文献类型：
--
作者：
Canals, JM;Pineda, JR;Alberch, J
控制亨廷顿病纹状体神经元选择性脆弱性的机制尚不清楚。脑源性神经营养因子（BDNF）保护纹状体神经元，并通过与神经元限制性沉默因子的相互作用受到亨廷顿蛋白的调节。在这里，我们证明了突变亨廷顿蛋白对BDNF的下调依赖于细胞培养物中CAG重复序列的长度和表达水平。为了分析这些BDNF变化在亨廷顿病中的功能作用，我们通过将bdnf（+/-）小鼠与R6/1小鼠交叉交配来破坏转基因小鼠模型中bdnf的表达。因此，我们比较了具有不同BDNF水平的突变亨廷顿蛋白的转基因小鼠。使用这种双突变小鼠系，我们表明，内源性BDNF的赤字调制亨廷顿病的病理。这种神经营养因子水平的降低会提前运动功能障碍的发作，并产生更严重的不协调运动。这种行为病理学与纹状体多巴胺和cAMP调节的磷蛋白-32阳性投射神经元的丢失相关。特别是，BDNF水平不足导致脑啡肽能纹状体投射神经元的特异性变性，这是亨廷顿病中受影响最严重的细胞。因此，BDNF水平的降低通过诱导纹状体脑啡肽能神经元的功能障碍而产生严重的运动功能障碍，在亨廷顿病中观察到的特定病理学中起关键作用。因此，外源性BDNF的施用可以延缓或阻止疾病进展。
The mechanism that controls the selective vulnerability of striatal neurons in Huntington's disease is unclear. Brain-derived neurotrophic factor (BDNF) protects striatal neurons and is regulated by Huntingtin through the interaction with the neuron-restrictive silencer factor. Here, we demonstrate that the downregulation of BDNF by mutant Huntingtin depends on the length and levels of expression of the CAG repeats in cell cultures. To analyze the functional effects of these changes in BDNF in Huntington's disease, we disrupted the expression of bdnf in a transgenic mouse model by cross-mating bdnf(+/-) mice with R6/1 mice. Thus, we compared transgenic mice for mutant Huntingtin with different levels of BDNF. Using this double mutant mouse line, we show that the deficit of endogenous BDNF modulates the pathology of Huntington's disease. The decreased levels of this neurotrophin advance the onset of motor dysfunctions and produce more severe uncoordinated movements. This behavioral pathology correlates with the loss of striatal dopamine and cAMP-regulated phosphoprotein-32-positive projection neurons. In particular, the insufficient levels of BDNF cause specific degeneration of the enkephalinergic striatal projection neurons, which are the most affected cells in Huntington's disease. This neuronal dysfunction can specifically be restored by administration of exogenous BDNF.Therefore, the decrease in BDNF levels plays a key role in the specific pathology observed in Huntington's disease by inducing dysfunction of striatal enkephalinergic neurons that produce severe motor dysfunctions. Hence, administration of exogenous BDNF may delay or stop illness progression.