Jayaweera Sanduni Wasana, Sahin Melisnur, Lundkvist Fabian, Leven Alice, Tereenstra Laura, Bäckman Joel, Bachhar Anushree, Bano Fouzia, Anan Intissar, Olofsson Anders
Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
J Biol Chem. 2025 Jan;301(1):108031. doi: 10.1016/j.jbc.2024.108031. Epub 2024 Nov 28.
Transthyretin (TTR) amyloidosis is a progressive disorder characterized by peripheral neuropathy, autonomic dysfunction, and cardiomyopathy. The precise mechanism by which TTR misfolds and forms fibrils in vivo remains incompletely understood, posing challenges to the development of effective therapeutics. In this study, we reveal that the recently identified nonnative pathological species of TTR (NNTTR), which is enriched in the plasma of ttr-val30met gene carriers, exhibits strong amyloidogenic properties, making it a promising therapeutic target. Notably, we demonstrate that NNTTR formation is dependent on an intermolecular disulfide bond and can be promoted by oxidative conditions while being effectively suppressed by reducing agents. The formation of this disulfide bond is incompatible with the native TTR fold, thereby necessitating structural flexibility. We further show that this required flexibility can be constrained using tetramer-stabilizing drugs, thereby suppressing NNTTR formation. Interestingly, the flexibility is also hindered by macromolecular crowding, and NNTTR formation is strongly suppressed by the high protein concentration in plasma. This suppression is released upon dilution, which thus promotes NNTTR formation in areas with lower protein content, highlighting a potential link to the interstitial space, brain, and vitreous body of the eye, where TTR-amyloid is frequently observed. In summary, we demonstrate that NNTTR displays strong amyloidogenic features, underscoring its potential as a therapeutic target. We identify the redox environment and macromolecular crowding as key modulatory factors. Our findings propose a mechanistic explanation for TTR misfolding and suggest a novel therapeutic approach.
转甲状腺素蛋白（TTR）淀粉样变性是一种进行性疾病，其特征为周围神经病变、自主神经功能障碍和心肌病。TTR在体内错误折叠并形成原纤维的确切机制仍未完全明确，这给有效治疗方法的开发带来了挑战。在本研究中，我们发现最近鉴定出的TTR非天然病理物种（NNTTR）在ttr-val30met基因携带者的血浆中富集，具有很强的淀粉样蛋白生成特性，使其成为一个有前景的治疗靶点。值得注意的是，我们证明NNTTR的形成依赖于分子间二硫键，在氧化条件下可被促进，而在还原剂作用下可被有效抑制。这种二硫键的形成与天然TTR折叠不兼容，因此需要结构灵活性。我们进一步表明，使用四聚体稳定药物可以限制这种所需的灵活性，从而抑制NNTTR的形成。有趣的是，大分子拥挤也会阻碍这种灵活性，血浆中的高蛋白浓度会强烈抑制NNTTR的形成。稀释后这种抑制作用会解除，从而促进蛋白质含量较低区域的NNTTR形成，这突出了与经常观察到TTR淀粉样蛋白的眼间质空间、大脑和玻璃体的潜在联系。总之，我们证明NNTTR具有很强的淀粉样蛋白生成特征，强调了其作为治疗靶点的潜力。我们确定氧化还原环境和大分子拥挤是关键调节因素。我们的发现为TTR错误折叠提出了一种机制解释，并提出了一种新的治疗方法。
