Novel therapeutic strategies targeting malleability of wild-type and mutant prions

Prion病总是致命的神经退行性疾病，发生在零星的， 传染性和遗传性，由野生型或突变型的转化引起 将细胞内的蛋白(PrPC)转变为自我传播、错误折叠的异构体 (统称为PrPSc)。目前还没有临床上有效的治疗任何形式的 普里恩病。 最近，化学筛查已经确定了不同类别的口服药物，这些药物可以显著 降低野生型PrPSc形成率，从而提高无病存活率 感染了普恩病毒的动物。然而，在每一个病例中，药物治疗都没有治愈普恩病毒感染， 这最终让接受治疗的动物不堪重负。在几乎所有情况下，替代PrPSc 在治疗过程中出现了构象，导致了Pron菌株的适应，在某些情况下，还导致了药物 抵抗。有趣的是，经过药物治疗的动物体内的普恩病毒可以恢复它们原来的菌株。 未经处理的宿主连续传代的特征和药物敏感性。此外，我们的 初步工作表明，由于出现了一种非正统的新药物，两种不同药物同时联合给药感染普里恩的小鼠未能产生协同效应。 对两种药物联合耐药但对两种药物单独敏感的菌株。已被占用 总而言之，这些观察表明，野生型普鲁恩具有高度的可塑性，即能够 在不同PrPSc构象之间来回切换以响应选择性 抗病毒药物治疗引起的压力。导致这一现象的分子机制 野生型普里子的延展性目前尚不清楚。目前也不清楚突变的普恩病毒， 与野生型一样具有延展性 普里恩。这项提案的总体目标是评估新的治疗策略， 合理靶向Prion的延展性，研究辅因子分子在药物诱导中的作用 蛋白菌种的适应性。具体地说，我们将：(1)评估交替口服药物的疗效 野生型Prion感染模型中的治疗方案；(2)确定辅因子选择是否发挥作用 在野生型普恩获得抗药性的机制中的作用；和(3)测试 口服药物方案对新的遗传性Pron病敲入小鼠模型的疗效。

Prion diseases are invariably fatal neurodegenerative disorders that occur in sporadic, infectious, and inherited forms, and are caused by the conversion of either wild-type or mutant versions of the cellular prion protein (PrPC) into self-propagating, misfolded conformers (collectively termed PrPSc). There is currently no clinically effective treatment for any form of prion disease. Recently, chemical screens have identified different classes of oral drugs that can significantly decrease the rate of wild-type PrPSc formation, and thereby increase disease-free survival in prion-infected animals. However, in each case, drug treatment did not cure prion infection, which eventually overwhelmed the treated animals. In almost all cases, an alternative PrPSc conformation emerged during therapy, causing prion strain adaptation and, in some cases, drug resistance. Interestingly, prions from drug-treated animals can recover their original strain characteristics and drug susceptibility during serial passage in untreated hosts. In addition, our preliminary work shows that simultaneous co-administration of two different drugs to prion-infected mice failed to create a synergistic effect due to the emergence of an unorthodox new strain that is resistant to the two-drug combination yet susceptible to both drugs alone. Taken together, these observations show that wild-type prions are highly malleable, i.e. able to switch back and forth between different PrPSc conformations in response to changes in selective pressure caused by anti-prion drug therapy. The molecular mechanism responsible for the malleability of wild-type prions is currently unknown. It is also unknown whether mutant prions, which specifically cause the inherited forms of prion disease, are as malleable as wild-type prions. The overall objectives of this proposal are to evaluate novel therapeutic strategies that rationally target prion malleability, and to study the role of cofactor molecules in drug-induced prion strain adaptation. Specifically, we will: (1) evaluate the efficacy of alternating oral drug regimens in a wild-type prion infection model; (2) determine whether cofactor selection plays a role in the mechanism by which wild-type prions acquire drug resistance; and (3) test the efficacy of oral drug regimens in new knock-in mouse models of inherited prion diseases.