Departament de Biologia Cel.lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, IDIBAPS, Casanova 143, E-08036 Barcelona, Spain.
Neurobiol Dis. 2009 Dec;36(3):461-9. doi: 10.1016/j.nbd.2009.08.012. Epub 2009 Sep 4.
Calcineurin is a serine/threonine phosphatase involved in the regulation of glutamate receptors signaling. Here, we analyzed whether the regulation of calcineurin protein levels and activity modulates the susceptibility of striatal neurons to excitotoxicity in R6/1 and R6/1:BDNF+/- mouse models of Huntington's disease. We show that calcineurin inhibition in wild-type mice drastically reduced quinolinic acid-induced striatal cell death. Moreover, calcineurin A and B were differentially regulated during disease progression with a specific reduction of calcineurin A protein levels and calcineurin activity at the onset of the disease in R6/1:BDNF+/- mice. Analysis of the conditional mouse model Tet/HD94 showed that mutant huntingtin specifically controls calcineurin A protein levels. Finally, calcineurin activation induced by intrastriatal quinolinic acid injection in R6/1 mouse was lower than in wild-type mice. Therefore, reduction of calcineurin activity by alteration of calcineurin A expression participates in the pathophysiology of Huntington's disease and contributes to the excitotoxic resistance observed in exon-1 mouse models.
钙调神经磷酸酶是一种丝氨酸/苏氨酸磷酸酶，参与谷氨酸受体信号的调节。在这里，我们分析钙调神经磷酸酶蛋白水平和活性的调节是否会影响亨廷顿病 R6/1 和 R6/1:BDNF+/- 小鼠模型中海马神经元对兴奋性毒性的易感性。我们发现，野生型小鼠中钙调神经磷酸酶的抑制作用大大降低了喹啉酸诱导的纹状体细胞死亡。此外，钙调神经磷酸酶 A 和 B 在疾病进展过程中受到不同的调节，在 R6/1:BDNF+/- 小鼠疾病发作时，钙调神经磷酸酶 A 蛋白水平和钙调神经磷酸酶活性特异性降低。对条件性小鼠模型 Tet/HD94 的分析表明，突变亨廷顿蛋白特异性控制钙调神经磷酸酶 A 蛋白水平。最后，纹状体注射喹啉酸诱导的钙调神经磷酸酶激活在 R6/1 小鼠中低于野生型小鼠。因此，钙调神经磷酸酶 A 表达改变导致钙调神经磷酸酶活性降低，参与亨廷顿病的病理生理学，并有助于在外显子 1 小鼠模型中观察到的兴奋性毒性抵抗。
