Notch-1 activation and dendritic atrophy in prion disease
Notch-1 activation and dendritic atrophy in prion disease
复制标题
DOI：
10.1073/pnas.0408612101
复制
发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
DeArmond, SJ
中科院分区：
文献类型：
--
作者：
Ishikura, N;Clever, JL;DeArmond, SJ
除了神经元空泡化和星形细胞肥大外，树突状萎缩是朊病毒病的一个突出特征。由于Notch-1表达的增加和细胞内结构域（NICD）的裂解释放抑制了树突的生长和成熟，我们测量了接种了Rocky Mountain Laboratory （RML）朊病毒的小鼠大脑中Notch-1的水平。新皮层中NICD水平升高，而刺激树突生长的β -连环蛋白水平不变。在潜伏期，致病朊病毒蛋白异构体、PrPSc和NICD水平在新皮层中同时升高。此外，Notch-1 mRNA水平的升高和NICD向细胞核的易位与退行性树突变化密切相关。在瘙痒病感染的神经母细胞瘤（ScN2a）细胞中，与未感染的对照（N2a）细胞相比，NICD水平升高。含有长神经丝蛋白的突起从N2a细胞表面延伸出来，而ScN2a细胞的突起则短得多。用Notch-1小干扰RNA转染ScN2a细胞可降低Notch-1 mRNA水平，降低NICD浓度，并恢复长过程表型。这些结果表明，神经元和ScN2a细胞中的PrPSc激活Notch-1切割，导致CNS树突萎缩和培养细胞表面突起萎缩。体内减少Notch-1激活是否可以预防甚至逆转朊病毒疾病的神经退行性变仍有待确定。
In addition to neuronal vacuolation and astrocytic hypertrophy, dendritic atrophy is a prominent feature of prion disease. Because increased Notch-1 expression and cleavage releasing its intracellular domain (NICD) inhibit both dendrite growth and maturation, we measured their levels in brains from mice inoculated with Rocky Mountain Laboratory (RML) prions. The level of NICD was elevated in the neocortex, whereas the level of beta-catenin, which stimulates dendritic growth, was unchanged. During the incubation period, levels of the disease-causing prion protein isoform, PrPSc, and NICD increased concomitantly in the neocortex. Additionally, increased levels of Notch-1 mRNA and translocation of NICD to the nucleus correlated well with regressive dendritic changes. In scrapie-infected neuroblastoma (ScN2a) cells, the level of NICD was elevated compared with uninfected control (N2a) cells. Long neurofilament protein-containing processes extended from the surface of N2a cells, whereas ScN2a cells had substantially shorter processes. Transfection of ScN2a cells with a Notch-1 small interfering RNA decreased Notch-1 mRNA levels, diminished NICD concentrations, and rescued the long process phenotype. These results suggest that PrPSc in neurons and in ScN2a cells activates Notch-1 cleavage, resulting in atrophy of dendrites in the CNS and shrinkage of processes on the surface of cultured cells. Whether diminishing Notch-1 activation in vivo can prevent or even reverse neurodegeneration in prion disease remains to be established.