PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins
PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins
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DOI：
10.1007/s00401-019-02114-9
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发表时间：
2020-03-01
影响因子：
12.7
通讯作者：
Walsh, Dominic M.
中科院分区：
文献类型：
--
作者：
Corbett, Grant T.;Wang, Zemin;Walsh, Dominic M.
神经退行性疾病是一个巨大的公共卫生问题，影响着全世界数千万人。几乎所有这些疾病的特征都是神经元蛋白的寡聚化和纤维化，并且人们对这些聚集体的治疗靶向产生了极大的兴趣。在这里，我们表明，α-突触核蛋白和tau蛋白的可溶性聚集体结合板固定的PrP在体外和小鼠皮层神经元，这种结合需要至少一个相同的N-末端位点，在可溶性A β聚集体结合。此外，tau、α-突触核蛋白和A β的可溶性聚集体引起功能性（LTP受损）和结构性（神经炎性营养不良）损害，并且当PrP被消融、敲低或当神经元用抗PrP阻断抗体预处理时，这些缺陷不存在。使用全人类实验范例，涉及：（1）表达或缺乏PRNP的同基因iPSC衍生神经元，以及（2）死于阿尔茨海默病，路易体痴呆和皮克病的个体大脑的水提取物，我们证明A β，α-突触核蛋白和tau蛋白对神经元具有毒性，需要PrP（c）。这些结果表明，PrP可能在各种晚期神经退行性疾病中发挥重要作用，并且PrP而不是单个疾病蛋白的治疗靶向可能对涉及一种以上蛋白质聚集的病症具有更多益处。
Neurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of alpha-synuclein and tau bind to plate-immobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble A beta aggregates bind. Moreover, soluble aggregates of tau, alpha-synuclein and A beta cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking PRNP, and (2) aqueous extracts from brains of individuals who died with Alzheimer's disease, dementia with Lewy bodies, and Pick's disease, we demonstrate that A beta, alpha-synuclein and tau are toxic to neurons in a manner that requires PrP (c). These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.