Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Int J Mol Sci. 2021 Jan 18;22(2):901. doi: 10.3390/ijms22020901.
A number of neurodegenerative diseases including prion diseases, tauopathies and synucleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformationally distinct, self-replicating states referred to as strains. Structural diversity of strains formed by tau, α-synuclein or prion proteins has been well documented. However, the question how different strains formed by the same protein elicit different clinical phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that posttranslational modifications are important players in defining strain-specific structures and disease phenotypes. This article put forward a new hypothesis referred to as substrate selection hypothesis, according to which individual strains selectively recruit protein isoforms with a subset of posttranslational modifications that fit into strain-specific structures. Moreover, it is proposed that as a result of selective recruitment, strain-specific patterns of posttranslational modifications are formed, giving rise to unique disease phenotypes. Future studies should define whether cell-, region- and age-specific differences in metabolism of posttranslational modifications play a causative role in dictating strain identity and structural diversity of strains of sporadic origin.
许多神经退行性疾病，包括朊病毒病、tau 病和突触核蛋白病，表现出多种临床表型。多种临床表型归因于与特定疾病相关的淀粉样蛋白的能力，即能够获得多种构象上不同的、自我复制的状态，称为株。tau、α-突触核蛋白或朊蛋白形成的株的结构多样性已得到充分证实。然而，由同一蛋白形成的不同株如何引发不同的临床表型这一问题仍知之甚少。本文综述了新出现的证据，表明翻译后修饰是定义株特异性结构和疾病表型的重要因素。本文提出了一个新的假设，称为底物选择假设，根据该假设，个体株选择性地招募具有一组翻译后修饰的蛋白同工型，这些修饰适合株特异性结构。此外，据推测，由于选择性招募，会形成株特异性的翻译后修饰模式，从而导致独特的疾病表型。未来的研究应该确定翻译后修饰代谢在细胞、区域和年龄特异性方面的差异是否在决定株的身份和散发性株的结构多样性方面起因果作用。
