Pedretti Rose, Wang Lanie, Yakubovska Anna, Zhang Qiongfang S, Nguyen Binh, Grodin Justin L, Masri Ahmad, Saelices Lorena
Center for Alzheimer's and Neurodegenerative Diseases, Department of Biophysics, Peter O'Donnell Jr Brain Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
JACC Basic Transl Sci. 2024 Jul 17;9(9):1088-1100. doi: 10.1016/j.jacbts.2024.05.013. eCollection 2024 Sep.
Amyloidogenic transthyretin (ATTR) amyloidosis is a relentlessly progressive disease caused by the misfolding and systemic accumulation of amyloidogenic transthyretin into amyloid fibrils. These fibrils cause diverse clinical phenotypes, mainly cardiomyopathy and/or polyneuropathy. Little is known about the aggregation of transthyretin during disease development and whether this has implications for diagnosis and treatment. Using the cryogenic electron microscopy structures of mature ATTR fibrils, we developed a peptide probe for fibril detection. With this probe, we have identified previously unknown aggregated transthyretin species in plasma of patients with ATTR amyloidosis. These species are large, non-native, and distinct from monomeric and tetrameric transthyretin. Observations from our study open many questions about the biology of ATTR amyloidosis and reveal a potential diagnostic and therapeutic target.
淀粉样前体蛋白转甲状腺素（ATTR）淀粉样变性是一种由淀粉样前体蛋白转甲状腺素错误折叠并系统性聚积成淀粉样纤维而导致的进行性疾病。这些纤维会引发多种临床表型，主要是心肌病和/或多发性神经病。关于转甲状腺素在疾病发展过程中的聚集情况以及这是否对诊断和治疗有影响，目前所知甚少。利用成熟ATTR纤维的低温电子显微镜结构，我们开发了一种用于纤维检测的肽探针。借助该探针，我们在ATTR淀粉样变性患者的血浆中鉴定出了此前未知的转甲状腺素聚集物种。这些物种体积大、非天然，且与单体和四聚体转甲状腺素不同。我们的研究观察结果引发了许多关于ATTR淀粉样变性生物学的问题，并揭示了一个潜在的诊断和治疗靶点。
