铜离子在朊蛋白聚集过程及其致病机理中所发挥作用的研究
摘要
朊蛋白是一类能侵染动物并在宿主细胞内复制的无免疫性疏水蛋白质。目前对于朊病毒疾病比较公认的致病机制是正常的富含α螺旋细胞型朊蛋白(PrPc)构象发生转变,形成富含β折叠片层结构并具有蛋白酶抗性的感染型朊蛋白(PrPSc)聚集。
许多证据证明大脑中淀粉样蛋白沉积与朊病毒疾病有关。有研究已经利用重组的PrP得到淀粉样纤维。除了淀粉样纤维聚集外,天然细胞型PrPc还能转变成为一种稳定的富含β折叠结构的寡聚体形态,并且这种来自于PrPSc的非纤维状的寡聚体具有较强的毒性。近年的证据表明可溶性寡聚体在神经退行性疾病中造成细胞功能的损伤。
已有的实验表明PrP能够特异地和铜离子结合并在体内可能作为一种铜离子结合蛋白存在。其中四个组氨酸残基结合位点位于60到91位的氨基酸残基区域,而最近的研究表明第96和111位的组氨酸残基也在PrP与铜离子结合过程中起到重要作用。证据表明铜离子能够调节朊病毒疾病的病理过程。
我们的研究结果发现铜离子是PrP寡聚过程中的关键因子。圆二色谱以及外源荧光实验结果揭示在弱酸性条件下铜离子促进的了PrP向富含β折叠的结构发生转变,而在偏中性条件下铜离子促进PrP形成无定型沉淀。通过分子筛色谱分离得到了PrP可溶性寡聚体并且利用原子力显微镜观察了寡聚体的大小及形态。寡聚体的平均直径为39±7nm。MTT实验和流式细胞术显示PrP的可溶性寡聚体对神经瘤母细胞SK-N-SH具有较强毒性并能诱导使其发生凋亡。荧光共聚焦显微镜显示PrP的可溶性寡聚体能够导致细胞内生的PrP发生聚集并转运到溶酶体中,并可能由此引发细胞凋亡信号。这些结果证明在生理酸性环境中,铜离子能够促进PrP形成具细胞毒性的可溶性寡聚体,并诱使神经细胞发生凋亡。
此外,铜离子还对PrP淀粉样纤维的形成起到调节作用。在接近生理的温和实验条件下,铜离子抑制了PrP淀粉样纤维的形成。光散射实验表明在铜离子参与情况下,PrP能够更快的形成较大颗粒的聚集。而ThT实验显示只有在pH7.0的中性环境中没有铜离子参与的条件下,PrP能够形成淀粉样纤维。铜离子的存在抑制了该条件下PrP纤维的形成。而在弱酸性条件下ThT荧光没有升高,表明没有淀粉样纤维形成。利用原子力显微镜观察了PrP纤维样聚集,其直径大约15nm,长度为300nm左右。
通过以上的研究,我们证明铜离子在PrP的聚集过程中起到重要作用。一方面铜离子能够促进PrP形成神经毒性的可溶性寡聚体,另一方面铜离子又能抑制体外典型PrP淀粉样纤维的形成。我们的研究结果提示铜离子可能在朊病毒疾病不同的病理过程中发挥不同的作用,并且为研究朊病毒疾病以及其它蛋白质构象病的发病机理提供有益的思路。
Prion is a kind of hydrophobic protein without imunity, which can infect human and animals and replicate in host cells. All of the prion diseases are accepted to share a common pathogenic mechanism, which based on the conversion of normal highα-helix containing PrPc into infectious and pathogenic PrPSc, which is the highly stable andβ-sheet rich isoform [1-3].
Accumulation of amyloid deposits in brains has been related to the prion diseases. It has been shown that aggregated amyloid fibrils derived from recombinant PrP in vitro caused disease in animal models [4]. Other than amyloid fibrils, the native state of PrPc is able to be converted into stable nonnative states with highβ-sheet content such as theβ-oligomer [5,6]. Also certain non-amyloidal oligomeric forms of PrP derived from PrPSc have been demonstrated toxicity [7]. Sufficient evidences accumulated over the last few years indicate that soluble oligomers are toxic species, which damage the cell functions in neurodegenerative diseases.
Earlier in vitro experiments revealed that the PrP specifically binds Cu2+[8-10] and this led to the proposal that PrP may function as a cuproprotein in vivo. The four histidine-containing octarepeats region of the PrP located between residues 60 and 91 was found binding Cu2+ in a cooperative manner [11], while recent researches indicated that residues 96 and 111 play important roles in binding Cu2+[12-14]. Accumulating evidences demonstrated that copper was able to modulate the pathogenesis of prion disease.
Our researches indicated that Cu2+ is a vital factor involved in the formation of PrP oligomers. Cu2+ triggered structural conversion of PrP (90-231) to P-sheet isoform was revealed by CD (circular dichroism) spectra and fluorescence measurement. Moreover, we obtained deposition of PrP at higher pH and isolated soluble oligomers by size exclusion chromatography at physiological acidic pH. AFM (atomic force microscope) images showed the morphology of oligomers with diameters of 39±7 nm. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and Flow Cytometry (FCM) demonstrated that oligomeric PrP induced significant damage and apoptosis of S-KN-SH cells. Using confocal microscopic techniques we found that oligomer induces the aggregation of endogenetic PrP, which is compartmentalized into the lysosomes where it might trigger pro-apoptotic cell death signals. This indicates that at physiological acidic environment Cu2+ promotes the formation of soluble PrP oligomers, which are cytotoxic and induce the apoptosis of neuron cells.
In addition, Cu2+ also modulates the PrP aggregation into amloidic fibrils. Cu2+ suppressed the fibration of PrP in physiological conditions. Scattering experiment showed that Cu2+ promoted the formation of larger PrP particles. But the fluorescence of ThT demonstrated that only in the neutral pH 7.0 condition free of Cu2+, PrP aggregated into amyloidic fibrils. While the presence of Cu2+ restrained the formation of PrP fibrils in the same condition. However in other weakly acidic conditions, the fluorescence of ThT did not increase, which indicated that the there was no PrP amyloidic fibrils. AFM confirmed the existence of PrP amyloid fibrils and showed the morphology with a diameter of about 15 nm and a length of about 300nm.
Our researches confirmed that Cu2+is a key factor in PrP aggregation. One hand, it promotes the formation of toxic soluble oligomers; on the other hand, Cu2+ suppresses the fibration of PrP. These results may indicate that Cu2+ plays different roles in different phases of the PrP pathogenesis, which may be beneficial for the pathogenesis of prion and other protein construction diseases.
许多证据证明大脑中淀粉样蛋白沉积与朊病毒疾病有关。有研究已经利用重组的PrP得到淀粉样纤维。除了淀粉样纤维聚集外,天然细胞型PrPc还能转变成为一种稳定的富含β折叠结构的寡聚体形态,并且这种来自于PrPSc的非纤维状的寡聚体具有较强的毒性。近年的证据表明可溶性寡聚体在神经退行性疾病中造成细胞功能的损伤。
已有的实验表明PrP能够特异地和铜离子结合并在体内可能作为一种铜离子结合蛋白存在。其中四个组氨酸残基结合位点位于60到91位的氨基酸残基区域,而最近的研究表明第96和111位的组氨酸残基也在PrP与铜离子结合过程中起到重要作用。证据表明铜离子能够调节朊病毒疾病的病理过程。
我们的研究结果发现铜离子是PrP寡聚过程中的关键因子。圆二色谱以及外源荧光实验结果揭示在弱酸性条件下铜离子促进的了PrP向富含β折叠的结构发生转变,而在偏中性条件下铜离子促进PrP形成无定型沉淀。通过分子筛色谱分离得到了PrP可溶性寡聚体并且利用原子力显微镜观察了寡聚体的大小及形态。寡聚体的平均直径为39±7nm。MTT实验和流式细胞术显示PrP的可溶性寡聚体对神经瘤母细胞SK-N-SH具有较强毒性并能诱导使其发生凋亡。荧光共聚焦显微镜显示PrP的可溶性寡聚体能够导致细胞内生的PrP发生聚集并转运到溶酶体中,并可能由此引发细胞凋亡信号。这些结果证明在生理酸性环境中,铜离子能够促进PrP形成具细胞毒性的可溶性寡聚体,并诱使神经细胞发生凋亡。
此外,铜离子还对PrP淀粉样纤维的形成起到调节作用。在接近生理的温和实验条件下,铜离子抑制了PrP淀粉样纤维的形成。光散射实验表明在铜离子参与情况下,PrP能够更快的形成较大颗粒的聚集。而ThT实验显示只有在pH7.0的中性环境中没有铜离子参与的条件下,PrP能够形成淀粉样纤维。铜离子的存在抑制了该条件下PrP纤维的形成。而在弱酸性条件下ThT荧光没有升高,表明没有淀粉样纤维形成。利用原子力显微镜观察了PrP纤维样聚集,其直径大约15nm,长度为300nm左右。
通过以上的研究,我们证明铜离子在PrP的聚集过程中起到重要作用。一方面铜离子能够促进PrP形成神经毒性的可溶性寡聚体,另一方面铜离子又能抑制体外典型PrP淀粉样纤维的形成。我们的研究结果提示铜离子可能在朊病毒疾病不同的病理过程中发挥不同的作用,并且为研究朊病毒疾病以及其它蛋白质构象病的发病机理提供有益的思路。
Prion is a kind of hydrophobic protein without imunity, which can infect human and animals and replicate in host cells. All of the prion diseases are accepted to share a common pathogenic mechanism, which based on the conversion of normal highα-helix containing PrPc into infectious and pathogenic PrPSc, which is the highly stable andβ-sheet rich isoform [1-3].
Accumulation of amyloid deposits in brains has been related to the prion diseases. It has been shown that aggregated amyloid fibrils derived from recombinant PrP in vitro caused disease in animal models [4]. Other than amyloid fibrils, the native state of PrPc is able to be converted into stable nonnative states with highβ-sheet content such as theβ-oligomer [5,6]. Also certain non-amyloidal oligomeric forms of PrP derived from PrPSc have been demonstrated toxicity [7]. Sufficient evidences accumulated over the last few years indicate that soluble oligomers are toxic species, which damage the cell functions in neurodegenerative diseases.
Earlier in vitro experiments revealed that the PrP specifically binds Cu2+[8-10] and this led to the proposal that PrP may function as a cuproprotein in vivo. The four histidine-containing octarepeats region of the PrP located between residues 60 and 91 was found binding Cu2+ in a cooperative manner [11], while recent researches indicated that residues 96 and 111 play important roles in binding Cu2+[12-14]. Accumulating evidences demonstrated that copper was able to modulate the pathogenesis of prion disease.
Our researches indicated that Cu2+ is a vital factor involved in the formation of PrP oligomers. Cu2+ triggered structural conversion of PrP (90-231) to P-sheet isoform was revealed by CD (circular dichroism) spectra and fluorescence measurement. Moreover, we obtained deposition of PrP at higher pH and isolated soluble oligomers by size exclusion chromatography at physiological acidic pH. AFM (atomic force microscope) images showed the morphology of oligomers with diameters of 39±7 nm. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and Flow Cytometry (FCM) demonstrated that oligomeric PrP induced significant damage and apoptosis of S-KN-SH cells. Using confocal microscopic techniques we found that oligomer induces the aggregation of endogenetic PrP, which is compartmentalized into the lysosomes where it might trigger pro-apoptotic cell death signals. This indicates that at physiological acidic environment Cu2+ promotes the formation of soluble PrP oligomers, which are cytotoxic and induce the apoptosis of neuron cells.
In addition, Cu2+ also modulates the PrP aggregation into amloidic fibrils. Cu2+ suppressed the fibration of PrP in physiological conditions. Scattering experiment showed that Cu2+ promoted the formation of larger PrP particles. But the fluorescence of ThT demonstrated that only in the neutral pH 7.0 condition free of Cu2+, PrP aggregated into amyloidic fibrils. While the presence of Cu2+ restrained the formation of PrP fibrils in the same condition. However in other weakly acidic conditions, the fluorescence of ThT did not increase, which indicated that the there was no PrP amyloidic fibrils. AFM confirmed the existence of PrP amyloid fibrils and showed the morphology with a diameter of about 15 nm and a length of about 300nm.
Our researches confirmed that Cu2+is a key factor in PrP aggregation. One hand, it promotes the formation of toxic soluble oligomers; on the other hand, Cu2+ suppresses the fibration of PrP. These results may indicate that Cu2+ plays different roles in different phases of the PrP pathogenesis, which may be beneficial for the pathogenesis of prion and other protein construction diseases.
引文
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