Pineda José R, Canals Josep M, Bosch Miquel, Adell Albert, Mengod Guadalupe, Artigas Francesc, Ernfors Patrik, Alberch Jordi
Departament de Biologia Cel.lular i Anatomia Patològica, Facultat de Medicina, Universitat de Barcelona, Spain.
J Neurochem. 2005 Jun;93(5):1057-68. doi: 10.1111/j.1471-4159.2005.03047.x.
Dysfunction of dopaminergic neurons may contribute to motor impairment in Huntington's disease. Here, we study the role of brain-derived neurotrophic factor (BDNF) in alterations of the nigrostriatal system associated with transgenics carrying mutant huntingtin. Using huntingtin-BDNF+/- double-mutant mice, we analyzed the effects of reducing the levels of BDNF expression in a model of Huntington's disease (R6/1). When compared with R6/1 mice, these mice exhibit an increased number of aggregates in the substantia nigra pars compacta. In addition, reduction of BDNF expression exacerbates the dopaminergic neuronal dysfunction seen in mutant huntingtin mice, such as the decrease in retrograde labelling of dopaminergic neurons and striatal dopamine content. However, mutant huntingtin mice with normal or lowered BDNF expression show the same decrease in the anterograde transport, number of dopaminergic neurons and nigral volume. In addition, reduced BDNF expression causes decreased dopamine receptor expression in mutant huntingtin mice. Examination of changes in locomotor activity induced by dopamine receptor agonists revealed that, in comparison with R6/1 mice, the double mutant mice exhibit lower activity in response to amphetamine, but not to apomorphine. In conclusion, these findings demonstrate that the decreased BDNF expression observed in Huntington's disease exacerbates dopaminergic neuronal dysfunction, which may participate in the motor disturbances associated with this neurodegenerative disorder.
多巴胺能神经元功能障碍可能导致亨廷顿舞蹈病的运动障碍。在此，我们研究脑源性神经营养因子（BDNF）在与携带突变型亨廷顿蛋白的转基因相关的黑质纹状体系统改变中的作用。使用亨廷顿蛋白-BDNF+/-双突变小鼠，我们分析了在亨廷顿舞蹈病（R6/1）模型中降低BDNF表达水平的影响。与R6/1小鼠相比，这些小鼠黑质致密部的聚集体数量增加。此外，BDNF表达的降低加剧了突变型亨廷顿蛋白小鼠中所见的多巴胺能神经元功能障碍，如多巴胺能神经元逆行标记减少和纹状体多巴胺含量降低。然而，BDNF表达正常或降低的突变型亨廷顿蛋白小鼠在顺行运输、多巴胺能神经元数量和黑质体积方面显示出相同程度的减少。此外，BDNF表达降低导致突变型亨廷顿蛋白小鼠中多巴胺受体表达减少。对多巴胺受体激动剂诱导的运动活动变化的检查显示，与R6/1小鼠相比，双突变小鼠对苯丙胺的反应活性较低，但对阿扑吗啡的反应活性无差异。总之，这些发现表明，在亨廷顿舞蹈病中观察到的BDNF表达降低加剧了多巴胺能神经元功能障碍，这可能参与了与这种神经退行性疾病相关的运动障碍。
