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首页> 外文期刊>Biochemistry >Inhibiting aggregation of alpha-synuclein with human single chain antibody fragments.
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Inhibiting aggregation of alpha-synuclein with human single chain antibody fragments.

机译：用人单链抗体片段抑制α-突触核蛋白的聚集。

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The alpha-synuclein protein has been strongly correlated with Parkinson's disease (PD) and is a major component of the hallmark Lewy body aggregates associated with PD. Two different mutations in the alpha-synuclein gene as well as increased gene dosage of wild-type alpha-synuclein all associate with early onset cases of PD; and transgenic animal models overexpressing alpha-synuclein develop PD symptoms. Alpha-synuclein, a natively unfolded protein, can adopt a number of different folded conformations including a beta-sheet form that facilitates formation of numerous aggregated morphologies, including long fibrils, spherical and linear protofibrils, and smaller aggregates or oligomers. The roles of the various morphologies of alpha-synuclein in the progression of PD are not known, and different species have been shown to be toxic. Here we show that single chain antibody fragments (scFv's) isolated from naive phage display antibody libraries can be used to control the aggregation of alpha-synuclein. We isolated an scFv with nanomolar affinity for monomeric alpha-synuclein (K(D) = 2.5 x 10(-8) M). When co-incubated with monomeric alpha-synuclein, the scFv decreased not only the rate of aggregation of alpha-synuclein, but also inhibited the formation of oligomeric and protofibrillar structures. The scFv binds the carboxyl terminal region of alpha-synuclein, suggesting that perturbation of this region can influence folding and aggregation of alpha-synuclein in vitro along with the previously identified hydrophobic core region of alpha-synuclein (residues 61-95, particularly residues 71-82). Since the scFv has been isolated from an antibody library based on human gene sequences, such scFv's can have potential therapeutic value in controlling aggregation of alpha-synuclein in vivo when expressed intracellularly as intrabodies in dopaminergic neurons.
机译：α-突触核蛋白已经与帕金森氏病（PD）密切相关，并且是与PD相关的标志性路易体聚集体的主要成分。 α-突触核蛋白基因中的两个不同突变以及野生型α-突触核蛋白的基因剂量增加均与PD的早期发病有关。过表达α-突触核蛋白的转基因动物模型会出现PD症状。 α-突触核蛋白是一种天然未折叠的蛋白质，可以采用多种不同的折叠构象，包括促进形成许多聚集形态的β-折叠形式，包括长原纤维，球形和线性原纤维以及较小的聚集体或寡聚体。尚不知道α-突触核蛋白的各种形态在PD进程中的作用，并且已证明不同物种具有毒性。在这里，我们显示从幼稚噬菌体展示抗体库中分离出的单链抗体片段（scFv）可用于控制α-突触核蛋白的聚集。我们分离了对单体α-突触核蛋白具有纳摩尔亲和力的scFv（K（D）= 2.5 x 10（-8）M）。当与单体α-突触核蛋白共同孵育时，scFv不仅降低了α-突触核蛋白的聚集速率，而且抑制了寡聚和原纤维结构的形成。 scFv结合α-突触核蛋白的羧基末端区域，表明该区域的扰动会影响α-突触核蛋白在体外的折叠和聚集以及先前确定的α-突触核蛋白的疏水核心区域（残基61-95，尤其是残基71） -82）。由于已经从基于人基因序列的抗体文库中分离了scFv，因此当scFv以多巴胺能神经元的细胞内形式在细胞内表达时，在体内控制α-突触核蛋白的聚集中可能具有潜在的治疗价值。

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