Bitan Gal, Tarus Bogdan, Vollers Sabrina S, Lashuel Hilal A, Condron Margaret M, Straub John E, Teplow David B
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
J Am Chem Soc. 2003 Dec 17;125(50):15359-65. doi: 10.1021/ja0349296.
Aberrant protein oligomerization is an important pathogenetic process in vivo. In Alzheimer's disease (AD), the amyloid beta-protein (Abeta) forms neurotoxic oligomers. The predominant in vivo Abeta alloforms, Abeta40 and Abeta42, have distinct oligomerization pathways. Abeta42 monomers oligomerize into pentamer/hexamer units (paranuclei) which self-associate to form larger oligomers. Abeta40 does not form these paranuclei, a fact which may explain the particularly strong linkage of Abeta42 with AD. Here, we sought to determine the structural elements controlling paranucleus formation as a first step toward the development of strategies for treating AD. Because oxidation of Met(35) is associated with altered Abeta assembly, we examined the role of Met(35) in controlling Abeta oligomerization. Oxidation of Met(35) in Abeta42 blocked paranucleus formation and produced oligomers indistinguishable in size and morphology from those produced by Abeta40. Systematic structural alterations of the C(gamma)(35)-substituent group revealed that its electronic nature, rather than its size (van der Waals volume), was the factor controlling oligomerization pathway choice. Preventing assembly of toxic Abeta42 paranuclei through selective oxidation of Met(35) thus represents a potential therapeutic approach for AD.
异常的蛋白质寡聚化是体内一个重要的致病过程。在阿尔茨海默病（AD）中，β-淀粉样蛋白（Aβ）形成神经毒性寡聚物。体内主要的Aβ异构体Aβ40和Aβ42具有不同的寡聚化途径。Aβ42单体寡聚形成五聚体/六聚体单元（副核），这些单元自组装形成更大的寡聚物。Aβ40不形成这些副核，这一事实可能解释了Aβ42与AD之间特别强的关联。在这里，我们试图确定控制副核形成的结构元件，作为开发治疗AD策略的第一步。由于Met(35)的氧化与Aβ组装的改变有关，我们研究了Met(35)在控制Aβ寡聚化中的作用。Aβ42中Met(35)的氧化阻止了副核的形成，并产生了在大小和形态上与Aβ40产生的寡聚物无法区分的寡聚物。C(γ)(35)-取代基的系统结构改变表明，控制寡聚化途径选择的因素是其电子性质，而不是其大小（范德华体积）。因此，通过Met(35)的选择性氧化来阻止有毒的Aβ42副核的组装，代表了一种潜在的AD治疗方法。
