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协核蛋白聚合是一种衍生性或祖先性质吗? 祖先序列重建揭示了同核蛋白聚合的逐步演变

Andrew Sam¹, Seungwoo Lee¹, Jordan Elliott¹

¹Department of Chemistry & Chemical Biology, Rutgers University, 123 Bevier Road, Piscataway, NJ 08854, USA.

bioRxiv : the preprint server for biology

|November 24, 2025

概括

蛋白质聚合,像帕金森氏症这样的神经退行性疾病的标志,随着时间的推移而演变. 祖先序列重建显示,α-synuclein (αSyn) 中纤维细胞的形成是一种获得的特征,而不是祖先的特征.

科学领域:

进化生物学是进化的生物学.
神经科学是一个神经科学.
生物化学生物化学

背景情况:

蛋白质聚合,特别是α-synuclein (αSyn),是神经退行性疾病的核心,如帕金森病.
αSyn聚合的进化起源和序列决定因素在很大程度上是未知的.
了解这些因素对于开发针对αSyn纤维细胞形成的治疗策略至关重要.

研究的目的:

研究同核蛋白蛋白家族内纤维状细胞形成能力的进化出现.
确定导致αSyn.聚合倾向的特定序列变化.
阐明序列进化,形状变化和纤维细胞形成之间的关系.

主要方法:

祖先序列重建 (ASR) 以推断和复活祖先的同核蛋白质.
遗传学分析以确定同核蛋白家族内的进化关系.
生物物理技术包括质谱和核磁共振来描述蛋白质结构和聚合.

主要成果:

根同核素,所有同核素的共同祖先,是非聚合的,表明聚合是一种进化的特征.
纤维细胞的形成出现在祖先的αβ节点上,存在于αSyn中,但在β-synuclein中被抑制.
进化序列的变化逐渐增加了单体结构复杂性,有利于纤维细胞的形成.
特定的残留物获取稳定了β弧核心并增强了原纤维相互作用,推动了αSyn聚合.

结论:

ASR为理解同核素聚合的演变提供了一个框架.
从非聚合到聚合形式的过渡涉及逐步序列修改.
进化压力重塑了同核蛋白单体,导致了αSyn纤维细胞形成和相关疾病的分子基础.

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