Altmeppen Hermann C, Puig Berta, Dohler Frank, Thurm Dana K, Falker Clemens, Krasemann Susanne, Glatzel Markus
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf Hamburg, Germany.
Am J Neurodegener Dis. 2012;1(1):15-31. Epub 2012 May 15.
A variety of physiological functions, not only restricted to the nervous system, are discussed for the cellular prion protein (PrP(C)). A prominent, non-physiological property of PrPC is the conversion into its pathogenic isoform (PrP(Sc)) during fatal, transmissible, and neurodegenerative prion diseases. The prion protein is subject to posttranslational proteolytic processing and these cleavage events have been shown i) to regulate its physiological functions, ii) to produce biologically active fragments, and iii) to potentially influence the course of prion disease. Here, we give an overview on the proteolytic processing under physiological and pathological conditions and critically review what is currently known about the three main cleavage events of the prion protein, namely α-cleavage, β-cleavage, and ectodomain shedding. The biological relevance of resulting fragments as well as controversies regarding candidate proteases, with special emphasis on members of the A-disintegrin-and-metalloproteinase (ADAM) family, will be discussed. In addition, we make suggestions aimed at facilitating clarity and progress in this important research field. The better understanding of this issue will not only answer basic questions in prion biology but will likely impact research on other neurodegenerative diseases as well.
本文讨论了细胞朊蛋白（PrP(C)）的多种生理功能，这些功能不仅局限于神经系统。PrPC一个显著的非生理特性是在致命性、传染性和神经退行性朊病毒疾病期间转化为其致病性异构体（PrP(Sc)）。朊蛋白会经历翻译后蛋白水解加工，这些切割事件已被证明：i）调节其生理功能；ii）产生生物活性片段；iii）可能影响朊病毒疾病的进程。在这里，我们概述了生理和病理条件下的蛋白水解加工情况，并批判性地回顾了目前关于朊蛋白三个主要切割事件的已知信息，即α-切割、β-切割和胞外域脱落。我们将讨论所得片段的生物学相关性以及关于候选蛋白酶的争议，特别强调解整合素和金属蛋白酶（ADAM）家族成员。此外，我们提出了一些建议，旨在促进这一重要研究领域的清晰度和进展。对这个问题的更好理解不仅将回答朊病毒生物学中的基本问题，也可能对其他神经退行性疾病的研究产生影响。
