Garcia Marta, Vanhoutte Peter, Pages Christiane, Besson Marie-Jo, Brouillet Emmanuel, Caboche Jocelyne
Neuronal Signaling and Gene Regulation, Centre National de la Recherche Scientifique/University Pierre et Marie Curie, Unité Mixte de Recherche 7102, 75005 Paris, France.
J Neurosci. 2002 Mar 15;22(6):2174-84. doi: 10.1523/JNEUROSCI.22-06-02174.2002.
Impairments in mitochondrial energy metabolism are thought to be involved in most neurodegenerative diseases, including Huntington's disease (HD). Chronic administration of 3-nitropropionic acid (3-NP), a suicide inhibitor of succinate dehydrogenase, causes prolonged energy impairments and replicates most of the pathophysiological features of HD, including preferential striatal degeneration. In this study, we analyzed one of the mechanisms that could account for this selective 3-NP-induced striatal degeneration. In chronically 3-NP-infused rats, the time course of motor behavioral impairments and histological abnormalities was determined. Progressive alterations of motor performance occurred after 3 d. By histological analysis and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labeling staining, we found a selective neurodegenerescence in the striatum, occurring first in its dorsolateral (DL) part. Activation of c-Jun N-terminal kinase (JNK) was analyzed from brain sections of these rats, using immunocytochemical detection of its phosphorylated form. Activation of JNK occurred progressively and selectively in the DL of the striatum and was followed by c-Jun activation and expression in the same striatal region. To elucidate the role of the JNK/c-Jun module in 3-NP-induced striatal degeneration, we then used primary striatal neurons in culture, in which we replicated neuronal death by application of 3-NP. We found strong nuclear translocation of activated JNK that was rapidly followed by phosphorylation of the transcription factor c-Jun. Overexpression of a dominant negative version of c-Jun, lacking its transactivation domain and phosphorylation sites for activated JNK, completely abolished 3-NP-induced striatal neurodegeneration. We thus conclude that a genetic program controlled by the JNK/c-Jun module is an important molecular event in 3-NP-induced striatal degeneration.
线粒体能量代谢受损被认为与包括亨廷顿舞蹈症（HD）在内的大多数神经退行性疾病有关。长期给予3-硝基丙酸（3-NP），一种琥珀酸脱氢酶的自杀性抑制剂，会导致长期的能量损伤，并重现HD的大多数病理生理特征，包括纹状体优先变性。在本研究中，我们分析了一种可以解释这种选择性3-NP诱导的纹状体变性的机制。在长期输注3-NP的大鼠中，确定了运动行为损伤和组织学异常的时间进程。3天后出现运动性能的渐进性改变。通过组织学分析和末端脱氧核苷酸转移酶介导的生物素化UTP缺口末端标记染色，我们发现纹状体中存在选择性神经退行性变，首先发生在其背外侧（DL）部分。使用免疫细胞化学检测其磷酸化形式，从这些大鼠的脑切片中分析c-Jun氨基末端激酶（JNK）的激活情况。JNK的激活在纹状体的DL中逐渐且选择性地发生，随后在同一纹状体区域出现c-Jun的激活和表达。为了阐明JNK/c-Jun模块在3-NP诱导的纹状体变性中的作用，我们随后使用了原代培养的纹状体神经元，在其中通过应用3-NP复制神经元死亡。我们发现激活的JNK有强烈的核转位，随后迅速出现转录因子c-Jun的磷酸化。缺乏其反式激活结构域和激活JNK的磷酸化位点的c-Jun显性负性变体的过表达完全消除了3-NP诱导的纹状体神经退行性变。因此，我们得出结论，由JNK/c-Jun模块控制的遗传程序是3-NP诱导的纹状体变性中的一个重要分子事件。
