A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies).
A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies).
复制标题
DOI：
10.1016/j.bbrc.2006.06.016
复制
发表时间：
2006-08
影响因子：
3.1
通讯作者：
K. Takano;Y. Kitao;R. Inagi;T. Momoi;T. Matsuyama;T. Miyata;Y. Yoneda;H. Iso;D. Stern;O. Hori;S. Ogawa
中科院分区：
文献类型：
--
作者：
K. Takano;Y. Kitao;R. Inagi;T. Momoi;T. Matsuyama;T. Miyata;Y. Yoneda;H. Iso;D. Stern;O. Hori;S. Ogawa
FENIB（具有神经丝氨酸蛋白酶抑制剂包涵体的家族性脑病）由内质网（ER）中突变型神经丝氨酸蛋白酶抑制剂的细胞内积累/聚合引起。过表达megsin（Tg梅格），一种新发现的丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）的转基因大鼠，表现出神经元内的α-酸性希夫（PAS）阳性夹杂物分布在整个大脑皮层，海马CA 1区，和黑质的深层。海马提取物从Tg梅格大鼠表现出ER应激蛋白的表达增加，半胱天冬酶-12和-3的激活，与神经元密度降低。在黑质多巴胺能神经元中也观察到增强的ER应激，同时神经元活力和运动协调性降低。在每种情况下，PAS阳性包涵体对megsin也呈阳性。这些数据表明，megsin的过度表达导致ER应激，最终导致PAS阳性包涵体的形成。Tg meg大鼠提供了一种新的FENIB模型，其中ER中丝氨酸蛋白酶抑制剂的积累诱导特定神经元群体的选择性功能障碍/丧失。
FENIB (familial encephalopathy with neuroserpin inclusion bodies) is caused by intracellular accumulation/polymerization of mutant neuroserpins in the endoplasmic reticulum (ER). Transgenic rats overexpressing megsin (Tg meg), a newly identified serine protease inhibitor (serpin), demonstrated intraneuronal periodic–acid Schiff (PAS)-positive inclusions distributed throughout deeper layers of cerebral cortex, CA1 of the hippocampus, and substantia nigra. Hippocampal extracts from Tg meg rats showed increased expression of ER stress proteins, and activation of caspases-12 and -3, associated with decreased neuronal density. Enhanced ER stress was also observed in dopaminergic neurons in the substantia nigra, in parallel with decreased neuronal viability and motor coordination. In each case, PAS-positive inclusions were also positive for megsin. These data suggest that overexpression of megsin results in ER stress, eventuating in the formation of PAS-positive inclusions. Tg meg rats provide a novel model of FENIB, where accumulation of serpins in the ER induces selective dysfunction/loss of specific neuronal populations.