Institut Pasteur, Unité de traffic membranaire et pathogenèse, 25 rue du Docteur Roux, 75724 Paris 5, Cedex 15, France.
Biochem J. 2013 May 15;452(1):1-17. doi: 10.1042/BJ20121898.
The misfolding and aggregation of specific proteins is a common hallmark of many neurodegenerative disorders, including highly prevalent illnesses such as Alzheimer's and Parkinson's diseases, as well as rarer disorders such as Huntington's and prion diseases. Among these, only prion diseases are 'infectious'. By seeding misfolding of the PrP(C) (normal conformer prion protein) into PrP(Sc) (abnormal disease-specific conformation of prion protein), prions spread from the periphery of the body to the central nervous system and can also be transmitted between individuals of the same or different species. However, recent exciting data suggest that the transmissibility of misfolded proteins within the brain is a property that goes way beyond the rare prion diseases. Evidence indicates that non-prion aggregates [tau, α-syn (α-synuclein), Aβ (amyloid-β) and Htt (huntingtin) aggregates] can also move between cells and seed the misfolding of their normal conformers. These findings have enormous implications. On the one hand they question the therapeutical use of transplants, and on the other they indicate that it may be possible to bring these diseases to an early arrest by preventing cell-to-cell transmission. To better understand the prion-like spread of these protein aggregates it is essential to identify the underlying cellular and molecular factors. In the present review we analyse and discuss the evidence supporting prion-like spreading of amyloidogenic proteins, especially focusing on the cellular and molecular mechanisms and their significance.
特定蛋白质的错误折叠和聚集是许多神经退行性疾病的共同特征，包括阿尔茨海默病和帕金森病等高发疾病，以及亨廷顿病和朊病毒病等罕见疾病。在这些疾病中，只有朊病毒病是“传染性的”。通过将 PrP(C)（正常构象朊蛋白）的错误折叠播种到 PrP(Sc)（朊病毒蛋白的异常疾病特异性构象）中，朊病毒从身体的外围传播到中枢神经系统，并且也可以在同一物种或不同物种的个体之间传播。然而，最近令人兴奋的研究数据表明，在大脑中错误折叠蛋白的可传播性超出了罕见的朊病毒病。有证据表明，非朊病毒聚集物[tau、α-syn（α-突触核蛋白）、Aβ（淀粉样-β）和 Htt（亨廷顿蛋白）聚集物]也可以在细胞之间移动，并引发其正常构象的错误折叠。这些发现具有巨大的意义。一方面，它们对移植的治疗用途提出了质疑，另一方面，它们表明通过防止细胞间传播，有可能使这些疾病尽早得到控制。为了更好地理解这些蛋白质聚集物的朊病毒样传播，识别潜在的细胞和分子因素至关重要。在本综述中，我们分析和讨论了支持淀粉样蛋白朊病毒样传播的证据，特别是重点讨论了细胞和分子机制及其意义。
