"Cyclophilin A" Enzymatic Effect on the Aggregation Behavior of 1N4R Tau Protein: An Overlooked Crucial Determinant that should be Re-considered in Alzheimer's Disease Pathogenesis.

Samira Ranjbar, Masomeh Mehrabi, Vali Akbari, Somayeh Pashaei, Reza Khodarahmi
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Abstract

Background: Neurodegenerative disorders like Alzheimer's disease (AD) involve the abnormal aggregation of tau protein, which forms toxic oligomers and amyloid deposits. The structure of tau protein is influenced by the conformational states of distinct proline residues, which are regulated by peptidyl-prolyl isomerases (PPIases). However, there has been no research on the impact of human cyclophilin A (CypA) as a PPIase on (non-phosphorylated) tau protein aggregation.

Methods: On the basis of these explanations, we used various spectroscopic techniques to explore the effects of CypA on tau protein aggregation behavior.

Results: We demonstrated the role of the isomerization activity of CypA in promoting the formation of tau protein amyloid fibrils with well-defined and highly ordered cross-β structures. According to the "cistauosis hypothesis," CypA's ability to enhance tau protein fibril formation in AD is attributed to the isomerization of specific proline residues from the trans to cis configuration. To corroborate this theory, we conducted refolding experiments using lysozyme as a model protein. The presence of CypA increased lysozyme aggregation and impeded its refolding process. It is known that proper refolding of lysozyme relies on the correct (trans) isomerization of two critical proline residues.

Conclusion: Thus, our findings confirmed that CypA induces the trans-to-cis isomerization of specific proline residues, ultimately leading to increased aggregation. Overall, this study highlights the emerging role of isomerization in tau protein pathogenesis in AD.

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"嗜环蛋白 A "对 1N4R Tau 蛋白聚集行为的酶促作用:阿尔茨海默病发病机制中应重新考虑的一个被忽视的关键决定因素
背景:阿尔茨海默病(AD)等神经退行性疾病涉及 tau 蛋白的异常聚集,从而形成有毒的低聚物和淀粉样沉积物。tau 蛋白的结构受不同脯氨酸残基构象状态的影响,而脯氨酸残基构象状态又受肽基-脯氨酰异构酶(PPIases)的调控。然而,目前还没有关于人类环嗜蛋白 A(CypA)作为一种 PPI 酶对(非磷酸化)tau 蛋白聚集的影响的研究:在这些解释的基础上,我们利用各种光谱技术探讨了 CypA 对 tau 蛋白聚集行为的影响:结果:我们证明了CypA的异构化活性在促进tau蛋白淀粉样纤维的形成中的作用,tau蛋白淀粉样纤维具有明确且高度有序的交叉β结构。根据 "cistauosis假说",CypA在AD中促进tau蛋白纤维形成的能力归因于特定脯氨酸残基从反式构型到顺式构型的异构化。为了证实这一理论,我们以溶菌酶为模型蛋白进行了重折叠实验。CypA 的存在增加了溶菌酶的聚集,阻碍了它的重折叠过程。众所周知,溶菌酶的正常重折叠依赖于两个关键脯氨酸残基的正确(反式)异构化:因此,我们的研究结果证实,CypA 会诱导特定脯氨酸残基发生反式-顺式异构化,最终导致聚集增加。总之,这项研究强调了异构化在注意力缺失症 tau 蛋白发病机制中的新作用。
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