Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration.
Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration.
复制标题
DOI：
10.1016/j.nbd.2011.02.014
复制
发表时间：
2011-07
影响因子：
6.1
通讯作者：
Gambello, Michael J.
中科院分区：
文献类型：
--
作者：
Reith, R. Michelle;Way, Sharon;McKenna, James, III;Haines, Katherine;Gambello, Michael J.
多发性硬化症（TSC）是一种神经遗传性疾病，通常会导致大脑异常，导致癫痫，发育迟缓和自闭症。TSC是由编码蛋白质hamartin（TSC 1）和tuberin（TSC 2）的基因中的失活突变引起的。这些蛋白质形成异源二聚体，其抑制雷帕霉素复合物1（mTORC 1）途径的哺乳动物靶点，控制翻译和细胞生长。任何一种蛋白质的缺失都会导致mTORC 1活化失调，这是TSC发病机制的一个重要方面。大约30%的TSC患者患有小脑病理学，这是知之甚少。为了研究TSC对小脑的影响，我们建立了一个小鼠模型，其中Tsc2基因从出生后第6天（P6）开始从浦肯野细胞中选择性删除。Tsc2的丢失导致浦肯野细胞大小的逐渐增加和随后的凋亡死亡。浦肯野细胞丢失主要是细胞类型特异性的，并与运动缺陷相关。免疫组化分析表明，内质网（ER）和氧化应激增加Tsc2空浦肯野细胞。通过用mTORC 1抑制剂雷帕霉素处理来挽救细胞死亡和ER应激表型。为了评估鼠浦肯野细胞丢失是否与人TSC相关，我们分析了TSC患者的死后小脑样本，检测到浦肯野细胞丢失占样本的一半。我们的研究结果建立了一个至关重要的作用，通过调节ER和氧化应激的浦肯野细胞存活的TSC复合物，并揭示了一个新的方面的TSC神经病理学。
Tuberous sclerosis complex (TSC) is a neurogenetic disorder that often causes brain abnormalities leading to epilepsy, developmental delay and autism. TSC is caused by inactivating mutations in either of the genes encoding the proteins hamartin (TSC1) and tuberin (TSC2). These proteins form a heterodimer that inhibits the mammalian target of rapamycin complex 1 (mTORC1) pathway, controlling translation and cell growth. Loss of either protein results in dysregulated mTORC1 activation, an important aspect of TSC pathogenesis. About thirty percent of TSC patients have cerebellar pathology that is poorly understood. To investigate the effects of TSC on the cerebellum, we created a mouse model in which the Tsc2 gene was selectively deleted from Purkinje cells starting at postnatal day 6 (P6). The loss of Tsc2 caused a progressive increase in Purkinje cell size and subsequent death from apoptosis. Purkinje cell loss was predominantly cell type specific and associated with motor deficits. Immunohistochemical analysis showed that both endoplasmic reticulum (ER) and oxidative stress were increased in Tsc2-null Purkinje cells. The cell death and ER stress phenotypes were rescued by treatment with the mTORC1 inhibitor rapamycin. To assess whether the murine Purkinje cell loss has a correlate to the human TSC, we analyzed postmortem cerebellum samples from TSC patients and detected Purkinje cell loss is half of the samples. Our results establish a critical role for the TSC complex in Purkinje cell survival by regulating ER and oxidative stress, and reveal a novel aspect of TSC neuropathology.
登录
查看更多内容
影响因子：
168.9
作者：
El-Hashemite, N;Zhang, HB;Kwiatkowski, DJ
通讯作者：
Kwiatkowski, DJ
影响因子：
3.1
作者：
Gordon, Neil
通讯作者：
Gordon, Neil
影响因子：
10.5
作者：
Inoki, K;Li, Y;Guan, KL
通讯作者：
Guan, KL
影响因子：
64.5
作者：
Hotamisligil GS
通讯作者：
Hotamisligil GS
影响因子：
1.5
作者：
Hernandez, Omar;Way, Sharon;Gambello, Michael J.
通讯作者：
Gambello, Michael J.