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嗅黏膜来源的 PMCA 生成的朊病毒导致家族性致死性失眠症患者的朊病毒病在小鼠中发生。

PMCA-generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice.

机构信息

Fondazione IRCCS Istituto Neurologico Carlo Besta, Division of Neurology 5 and Neuropathology, Milan, Italy.

Centro de Investigación en Sanidad Animal (CISA-INIA), Valdeolmos, Madrid, Spain.

出版信息

Elife. 2021 Apr 14;10:e65311. doi: 10.7554/eLife.65311.

DOI:10.7554/eLife.65311
PMID:33851575
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8064759/
Abstract

BACKGROUND

Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. In 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA).

METHODS

In this work, we have challenged PMCA-generated products obtained from OM and brain homogenate of FFI patients in BvPrP-Tg407 transgenic mice expressing the bank vole prion protein to test their ability to induce prion pathology.

RESULTS

All inoculated mice developed mild spongiform changes, astroglial activation, and PrPSc deposition mainly affecting the thalamus. However, their neuropathological alterations were different from those found in the brain of BvPrP-Tg407 mice injected with raw FFI brain homogenate.

CONCLUSIONS

Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious.

FUNDING

This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer's Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (SPEEDY) to FM; by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) to JMT and JCE; AM-M was supported by a fellowship from the INIA (FPI-SGIT-2015-02).

摘要

背景

致死性家族失眠症（FFI）是一种遗传性朊病毒病，由朊病毒蛋白基因（PRNP）中的 D178N 突变与 PRNP 129 位的蛋氨酸相结合引起。2017 年，我们已经证明从 FFI 患者的嗅黏膜（OM）中提取的样本含有可通过蛋白错误折叠循环扩增（PMCA）检测到的 PrPSc 痕迹。

方法

在这项工作中，我们用从 FFI 患者的 OM 和脑匀浆中获得的 PMCA 产物对 BvPrP-Tg407 转基因小鼠进行了挑战，该小鼠表达bank vole 朊病毒蛋白，以测试它们诱导朊病毒病的能力。

结果

所有接种的小鼠均出现轻度海绵状改变、星形胶质细胞激活和 PrPSc 沉积，主要影响丘脑。然而，它们的神经病理学改变与用原始 FFI 脑匀浆注射的 BvPrP-Tg407 小鼠的大脑中发现的改变不同。

结论

尽管存在一些实验限制，但我们表明 FFI 患者 OM 中存在的 PrPSc 具有潜在的传染性。

资助

这项工作得到了意大利卫生部（GR-2013-02355724 和 Ricerca Corrente）、MJFF、ALZ、英国阿尔茨海默氏症研究协会和 Weston 脑研究所（BAND2015）以及 Euronanomed III（SPEEDY）的部分资助（授予 FM）；西班牙经济与竞争力部（AGL2016-78054-R [AEI/FEDER，UE]）资助 JMT 和 JCE；AM-M 得到了 INIA（FPI-SGIT-2015-02）奖学金的支持。

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