金属蛋白酶 ADAM10 蛋白水解细胞表面释放（“脱落”）朊病毒蛋白 (PrP)（一种广泛表达的 GPI 锚定糖蛋白）对动物和体外模型中的神经退行性疾病和其他疾病有影响。最近使用后者的研究也表明脱落 PrP (sPrP) 是细胞间通讯的配体，并且关键参与与 PrP 相关的生理任务。尽管预期这是一个进化保守事件，并且虽然可溶形式的 PrP 存在于人体组织和体液中，但对于人体来说，迄今为止，无论是蛋白水解 PrP 脱落及其切割位点还是 ADAM10 的参与或该过程的生物学相关性都尚未得到证实。在这项研究中，sPrP 特异性抗体的切割位点预测和生成（以及详细表征）使我们能够将在酪氨酸 226 处切割的 PrP 识别为人类中生理且明显严格依赖 ADAM10 的脱落形式。利用细胞系、神经干细胞和脑类器官，我们发现 PrP 结合配体可以刺激人 PrP 的脱落，而不需要靶向蛋白酶，这可能会开辟新的治疗前景。针对人类 sPrP 的位点特异性抗体还可检测牛、羊和鹿大脑中的脱落形式，因此在所有自然受致命和传染性朊病毒疾病影响的最相关物种中也可检测到。在人类和动物朊病毒疾病中，以及在阿尔茨海默氏病患者中，sPrP从生理弥散组织模式重新定位，与各自病理状况特有的错误折叠蛋白的细胞外聚集沉积物密切相关。本文介绍的发现和研究工具将加速对 PrP 脱落（作为一个过程）和 sPrP（作为释放因子）在神经退行性变及其他方面的作用的新见解。© 2024。作者。

Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.© 2024. The Author(s).