Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina, Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Universitat de Barcelona, Barcelona, Spain.
Neuropathol Appl Neurobiol. 2012 Jun;38(4):311-21. doi: 10.1111/j.1365-2990.2011.01214.x.
3-Nitropropionic acid (3-NP) is a toxin that replicates most of the clinical and pathophysiological symptoms of Huntington's disease, inducing neurodegeneration in the striatum due to the inhibition of mitochondrial succinate dehydrogenase. Different pathways have been implicated in the cell death induced by 3-NP in rodents. One of them is the Jun-N-terminal kinase (JNK) pathway, which may play a role in the neurodegenerative process in different diseases. Moreover, the lack of one isoform of JNK (JNK3) has been associated with neuroprotection in different experimental models of neurodegeneration. Therefore, in the present study the role of JNK3 in the experimental Huntington's model induced by 3-NP administration was evaluated.
3-NP was intraperitoneally administered once a day for 3 days to wild-type and Jnk3-null mice. Coronal brain sections were used to determine cell death and astrogliosis in striatum. Western blots were performed to determine the involvement of different pathways in both wild-type and Jnk3-null mice.
Although JNK activation was observed following 3-NP administration, the results indicate that the lack of JNK3 does not confer neuroprotection against 3-NP toxicity. Thus, other pathways must be involved in the neurodegeneration induced in this model. One of the possible pathways towards 3-NP-induced apoptosis could involve the calpains, as their activity was increased in wild-type and Jnk3-null mice.
Although JNK3 is a key protein involved in cell death in different neurodegenerative diseases, the present study demonstrates that the lack of JNK3 does not confer neuroprotection against 3-NP-induced neuronal death.
3-硝基丙酸（3-NP）是一种毒素，可复制亨廷顿病的大部分临床和病理生理学症状，由于抑制线粒体琥珀酸脱氢酶，导致纹状体神经退行性变。在啮齿动物中，3-NP 诱导的细胞死亡涉及不同的途径。其中之一是 Jun-N-末端激酶（JNK）途径，它可能在不同疾病的神经退行性过程中发挥作用。此外，JNK 的一种同工型（JNK3）缺失与不同的神经退行性变实验模型中的神经保护有关。因此，本研究评估了 JNK3 在 3-NP 给药诱导的实验性亨廷顿病模型中的作用。
3-NP 每天腹膜内注射一次，连续 3 天，用于野生型和 Jnk3 基因敲除小鼠。使用冠状脑切片来确定纹状体中的细胞死亡和星形胶质细胞增生。进行 Western blot 以确定不同途径在野生型和 Jnk3 基因敲除小鼠中的参与情况。
尽管观察到 3-NP 给药后 JNK 激活，但结果表明 JNK3 的缺失不能赋予对 3-NP 毒性的神经保护作用。因此，其他途径必须参与该模型诱导的神经退行性变。可能涉及钙蛋白酶的途径之一，因为它们的活性在野生型和 Jnk3 基因敲除小鼠中增加。
尽管 JNK3 是不同神经退行性疾病中细胞死亡的关键蛋白，但本研究表明 JNK3 的缺失不能赋予对 3-NP 诱导的神经元死亡的神经保护作用。
