Fatal transmissible amyloid encephalopathy: a new type of prion disease associated with lack of prion protein membrane anchoring.
Fatal transmissible amyloid encephalopathy: a new type of prion disease associated with lack of prion protein membrane anchoring.
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DOI：
10.1371/journal.ppat.1000800
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发表时间：
2010-03-05
期刊：
影响因子：
6.7
通讯作者：
Jeffrey M
中科院分区：
文献类型：
--
作者：
Chesebro B;Race B;Meade-White K;Lacasse R;Race R;Klingeborn M;Striebel J;Dorward D;McGovern G;Jeffrey M
Prion病是一种人类和动物的致死性神经退行性疾病，其特征是灰质海绵样变和聚集的、错误折叠的、抗蛋白酶的Prion蛋白(PrPres)的聚集。PrPres可以淀粉样蛋白形式和/或非淀粉样蛋白形式沉积在大脑中，由宿主编码的蛋白酶敏感PrP(PrPsen)衍生，PrPsen是一种通常由糖基磷脂酰肌醇(GPI)锚定在质膜上的蛋白质。以前，使用只表达无锚定PrP的杂合转基因小鼠，我们发现典型的临床瘙痒病需要PrP锚定在细胞膜上。然而，在目前的实验中，与只表达锚定PrP的非转基因小鼠相比，使用表达两倍以上无锚定PrP的纯合子转基因小鼠，瘙痒病感染诱导了一种新的致命疾病，具有独特的临床症状和改变的神经病理。转基因小鼠的脑组织具有很高的感染性，组织病理学显示致密的淀粉样蛋白PrPres斑块沉积，没有灰质海绵。相比之下，感染的非转基因小鼠有弥漫性的非淀粉样蛋白PrPres沉积，并有明显的灰质海绵状病变。脑移植研究表明，PrPsen的锚定表达是普恩病毒感染期间灰质海绵体形成所必需的。此外，在感染的转基因小鼠中进行的电子和光学显微镜研究显示了几个典型的普恩疾病中没有的致病过程，包括大脑淀粉样血管病变和血管周围神经纤维的超微结构变化。这些发现类似于某些人类家族性Pron疾病以及非Prion人类神经退行性疾病，如阿尔茨海默病。Pron病，又称传染性海绵状脑病，是人和动物的传染性致死性神经退行性疾病。Prion病的一个主要特征是将正常的宿主蛋白Prion蛋白(PrP)折叠和聚集成与疾病相关的形式，这可能会导致脑损伤。在未感染的个体中，正常的PrP通过糖-磷酸-脂连接分子锚定在外细胞膜上。在本报告中，我们发现PrP基因缺失的小鼠感染PrP蛋白会导致一种新型的致命性神经退行性疾病。这种疾病表现出阿尔茨海默病和家族性淀粉样脑病对脑细胞和脑血管的损伤机制。相比之下，没有观察到在普恩病毒疾病中看到的典型的海绵状脑损伤。这些结果表明，PrP膜锚定的存在或不存在可以影响PrP感染后所见的神经变性的类型。
Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres). PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen), a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI). Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease. Prion diseases, also known as transmissible spongiform encephalopathies, are infectious fatal neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated form which may contribute to brain damage. In uninfected individuals, normal PrP is anchored to the outer cell membrane by a sugar-phosphate-lipid linker molecule. In the present report we show that prion infection of mice expressing PrP lacking the anchor can result in a new type of fatal neurodegenerative disease. This disease displays mechanisms of damage to brain cells and brain blood vessels found in Alzheimer's disease and in familial amyloid brain diseases. In contrast, the typical sponge-like brain damage seen in prion diseases was not observed. These results suggest that presence or absence of PrP membrane anchoring can influence the type of neurodegeneration seen after prion infection.
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影响因子：
12.7
作者：
JEFFREY, M;SCOTT, JR;FRASER, H
通讯作者：
FRASER, H
DOI：
10.1111/j.1365-2990.1997.tb01191.x
发表时间：
1997-04-01
影响因子：
5
作者：
Jeffrey, M;Goodsir, CM;Fraser, JR
通讯作者：
Fraser, JR
DOI：
10.1073/pnas.93.2.744
发表时间：
1996-01-23
影响因子：
11.1
作者：
Ghetti, B;Piccardo, P;Tagliavini, F
通讯作者：
Tagliavini, F
影响因子：
3.8
作者：
DIRINGER, H;EHLERS, B
通讯作者：
EHLERS, B
影响因子：
5.4
作者：
Doh-Ura, K;Ishikawa, K;Iwaki, T
通讯作者：
Iwaki, T