Increased apoptosis arising from increased expression of the Alzheimer's disease-associated presenilin-2 mutation (N141I).
Increased apoptosis arising from increased expression of the Alzheimer's disease-associated presenilin-2 mutation (N141I).
复制标题
DOI：
10.1083/jcb.139.2.485
复制
发表时间：
1997-10-20
期刊：
影响因子：
--
通讯作者：
Monteiro MJ
中科院分区：
文献类型：
--
作者：
Janicki S;Monteiro MJ
早老素1和2（PS-1和PS-2）基因突变与早发性阿尔茨海默病（AD）的发生有关。由于既不知道任何早老素的正常功能，也不知道为什么突变会导致疾病，我们研究了野生型，截短型和突变型PS-2在HeLa细胞中表达后的特性。虽然HeLa细胞强烈倾向于继续有丝分裂，PS-2的表达诱导程序性细胞死亡（凋亡）。通过末端脱氧核苷酸转移酶缺口末端标记（TUNEL）和PS-2表达的双重染色以及随时间推移追踪绿色荧光蛋白标记的PS-2，获得细胞凋亡的直接证据。缺失分析表明，PS-2的NH 2-末端残基少至166个就足以用于内质网（ER）定位和凋亡。此外，与野生型PS-2相比，AD相关的PS-2错义突变（N141 I）更有效地诱导细胞死亡，尽管突变体蛋白质积累较低。早老素在其他几种细胞系和转基因小鼠中的表达伴随着快速的蛋白质切割而不诱导细胞死亡。相反，在HeLa细胞中表达的PS-2不被切割，并且发生细胞死亡。我们推测，全长但不裂解PS-2可能是重要的调节或诱导细胞凋亡。
Mutations in the genes for presenilin 1 and 2 (PS-1 and PS-2) have been linked to development of early-onset Alzheimer's disease (AD). As neither the normal function of either presenilin is known nor why mutations cause disease, we examined the properties of wild-type, truncated, and mutant PS-2 upon expression in HeLa cells. Although HeLa cells are strongly predisposed to continued mitosis, expression of PS-2 induced programmed cell death (apoptosis). Direct evidence for apoptosis was obtained by double staining for terminal deoxynucleotide transferase nick end labeling (TUNEL) and PS-2 expression and by following green fluorescent protein–tagged PS-2 over time. Deletion analysis indicates that as little as 166 NH2-terminal residues of PS-2 are sufficient for endoplasmic reticulum (ER) localization and apoptosis. Moreover, the AD- associated PS-2 missense mutation (N141I) more efficiently induced cell death compared to wild-type PS-2 despite lower mutant protein accumulation. Expression of the presenilins in several other cell lines and transgenic mice has been accompanied by rapid protein cleavage without the induction of cell death. In contrast, PS-2 expressed in HeLa cells was not cleaved, and cell death occurred. We hypothesize that full-length but not cleaved PS-2 may be important in the regulation or induction of apoptosis.