Ferri Alberto, Nencini Monica, Battistini Stefania, Giannini Fabio, Siciliano Gabriele, Casali Carlo, Damiano Maria G, Ceroni Mauro, Chiò Adriano, Rotilio Giuseppe, Carrì Maria Teresa
Ist. di Neuroscienze CNR, Sez. Psicobiologia e Psicofarmacologia, Rome, Italy.
J Neurochem. 2004 Sep;90(5):1237-42. doi: 10.1111/j.1471-4159.2004.02588.x.
Calcineurin (CaN) is a Ser/Thr protein phosphatase involved in a wide range of cellular responses to calcium mobilizing signals. Previous evidence supports the notion that calcineurin is oxidatively inhibited by mutant Cu, Zn superoxide dismutase (SOD1) typical of familial ALS patients in vitro and in transgenic mice. We report that calcineurin activity is markedly inhibited in lymphocytes from 37 sporadic, eight familial ALS patients and an asymptomatic subject carrying an SOD1 mutation as compared to 28 healthy controls. Two other healthy subjects, heterozygous for the D90A mutation from a recessive pedigree, have normal calcineurin activity. Immunoreactive CaN protein, age, sex and riluzole treatment are not related to calcineurin activity in samples from patients. However, we have observed a marked increase in total protein oxidation in extracts from ALS lymphocytes, as compared to extracts from control subjects. These data confirm that modification of calcineurin activity and possibly of calcineurin-mediated pathways of signal transduction (including modulation of apoptotic neuronal death) may contribute to the pathogenesis of ALS.
钙调神经磷酸酶（CaN）是一种丝氨酸/苏氨酸蛋白磷酸酶，参与细胞对钙动员信号的多种反应。先前的证据支持这样一种观点，即在体外和转基因小鼠中，钙调神经磷酸酶受到家族性肌萎缩侧索硬化症（ALS）患者典型的突变型铜锌超氧化物歧化酶（SOD1）的氧化抑制。我们报告，与28名健康对照相比，37名散发性、8名家族性ALS患者以及一名携带SOD1突变的无症状受试者的淋巴细胞中，钙调神经磷酸酶活性明显受到抑制。另外两名来自隐性家系的D90A突变杂合健康受试者，其钙调神经磷酸酶活性正常。在患者样本中，免疫反应性CaN蛋白、年龄、性别和利鲁唑治疗与钙调神经磷酸酶活性无关。然而，与对照受试者的提取物相比，我们观察到ALS淋巴细胞提取物中的总蛋白氧化显著增加。这些数据证实，钙调神经磷酸酶活性的改变以及可能由钙调神经磷酸酶介导的信号转导途径（包括对凋亡性神经元死亡的调节）的改变可能有助于ALS的发病机制。
