Prion Transport Across the Blood-Brain Barrier

朊病毒疾病代表了一组不同的传染性神经退行性疾病。接受度最高的 一种假说认为，感染因子（称为朊病毒）是一种正常蛋白质的错误折叠形式， 缺乏核酸的。当传染性形式（PrPsc）转化为正常形式时， 在羊瘙痒病中，朊病毒是一种糖蛋白， 30,000兆瓦的蛋白质核心要产生中枢神经系统（CNS）疾病，PrPsc必须进入大脑， 这需要它通过血脑屏障（BBB）。本研究的主要目的是确定 PrPsc如何穿过血脑屏障，并最终开发出阻断进入血脑屏障的治疗策略。 从而预防朊病毒病。我们和其他人的工作表明， 糖蛋白（如小麦胚芽凝集素和gp 120，艾滋病病毒的外壳）通过血脑屏障， 诱导吸收性内吞作用（AE）。我们假设PrPsc通过以下机制穿过BBB： 的AE。该假设提供了无细胞PrPsc和PrPsc通过BBB的机制。 感染的免疫细胞，并解释了如何中枢神经系统的某些区域，如胸脊髓，可以 尤其是针对。虽然我们的工作假设是无细胞PrPsc是主要机制，但这些研究表明， 实验的目的是确定在何种程度上进入的其他可能的机制， CNS（免疫细胞转移，逆行脾神经传递，跨膜扩散，饱和 载体/受体介导的转运、通过细胞外途径的渗漏）对于PrPsc是可操作的。我们将 使用高度纯化、放射性标记的PrPsc测定转运和分布到脑中的速率 区域，脊髓和CSF，脾神经和免疫细胞在神经侵袭中的作用，以及体外 模型来检查穿过脑内皮细胞的细胞生物学。 摘要：朊病毒引起罕见的，但毁灭性的疾病，如疯牛病。引起疾病， 朊病毒必须穿过血脑屏障才能进入大脑。我们将确定朊病毒如何穿过血脑屏障。 了解了朊病毒如何进入大脑，就可以制定出预防朊病毒疾病的策略。

Prion diseases represent a diverse group of infectious neurodegenerative disorders. The most accepted hypothesis is that the infectious agent (termed prion) is a misfolded version of a normal protein completely devoid of nucleic acids. Disease is propagated when the infectious form (PrPsc) converts the normal form (PrPc) to the infectious form by reversibly combining with it. In scrapie, the prion is a glycoprotein with about a 30,000 MW protein core. To produce central nervous system (CNS) disease, PrPsc must enter the brain, which requires it negotiate the blood-brain barrier (BBB). The major goal of this research is to determine how PrPsc crosses the BBB and ultimately to develop therapeutic strategies for blocking passage into the CNS and so preventing prion disease. Work by us and others have shown that other neurotoxic glycoproteins (such as wheatgerm agglutinin and gp120, the coat of the AIDS virus) cross the BBB by inducing absorptive endocytosis (AE). We hypothesize that PrPsc crosses the BBBthrough the mechanism of AE. This hypothesis provides a mechanism for passage across the BBB of cell-free PrPsc and of PrPsc- infected immune cells and explains how some regions of the CNS, such as the thoracic spinal cord, can be especially targeted. Although our working hypothesis is that cell-free PrPsc is the major mechanism , these experiments are designed to determine the extent to which the other possible mechanisms of entry into the CNS (immune cell transfer, retrograde splenic nerve transmission, transmembrane diffusion, saturable carrier/receptor mediated transport, leakage via extracellular pathways) are operational for PrPsc. We will use highly purified, radioactively labeled PrPsc to determine rates of transport and distribution into brain regions, spinal cord, and CSF, the role of splenic nerves and immune cells in neuroinvasion, and in vitro models to examine the cellular biology of passage across the brain endothelial cell. Lay Summary: Prions cause rare, but devastating, diseases such as mad cow disease. To cause disease, prions must cross the blood-brain barrier to enter the brain. We will determine how prions cross the BBB. Knowing how prions enter the brain should lead to strategies on how to prevent prion diseases.