Espay Alberto J, Lees Andrew J, Cardoso Francisco, Frucht Steven J, Erskine Daniel, Sandoval Ivette M, Bernal-Conde Luis Daniel, Sturchio Andrea, Imarisio Alberto, Hoffmann Christian, Montemagno Kora T, Milovanovic Dragomir, Halliday Glenda M, Manfredsson Fredric P
James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
The National Hospital, Queen Square and Reta Lila Weston Institute for Neurological Studies University College London, London, UK.
Parkinsonism Relat Disord. 2025 Feb;131:107256. doi: 10.1016/j.parkreldis.2024.107256. Epub 2024 Dec 27.
The α-synuclein seed amplification assay (αSyn-SAA) sensitively detects Lewy pathology, the amyloid state of α-synuclein, in the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD). The αSyn-SAA harnesses the physics of seeding, whereby a superconcentrated solution of recombinant α-synuclein lowers the thermodynamic threshold (nucleation barrier) for aggregated α-synuclein to act as a nucleation catalyst ("seed") to trigger the precipitation (nucleation) of monomeric α-synuclein into pathology. This laboratory setup increases the signal for identifying a catalyst if one is present in the tissue examined. The result is binary: positive, meaning precipitation occurred, and a catalyst is present, or negative, meaning no precipitation, therefore no catalyst. Since protein precipitation via seeding can only occur at a concentration many-fold higher than the human brain, laboratory-elicited seeding does not mean human brain seeding. We suggest that a positive αSyn-SAA reveals the presence of pathological α-synuclein but not the underlying etiology for the precipitation of monomeric α-synuclein into its pathological form. Thus, a positive αSyn-SAA supports a clinical diagnosis of PD but cannot inform disease pathogenesis, ascertain severity, predict the rate of progression, define biology or biological subtypes, or monitor treatment response.
α-突触核蛋白种子扩增分析（αSyn-SAA）能够灵敏地检测帕金森病（PD）患者脑脊液（CSF）中路易氏病理改变，即α-突触核蛋白的淀粉样状态。αSyn-SAA利用了种子生成的物理原理，即重组α-突触核蛋白的超浓缩溶液降低了聚集的α-突触核蛋白作为成核催化剂（“种子”）触发单体α-突触核蛋白沉淀（成核）成为病理状态的热力学阈值（成核屏障）。如果在被检查的组织中存在催化剂，这种实验室设置会增加识别催化剂的信号。结果是二元的：阳性意味着发生了沉淀，存在催化剂；阴性意味着没有沉淀，因此没有催化剂。由于通过种子生成实现的蛋白质沉淀只能在比人脑浓度高许多倍的情况下发生，实验室诱导的种子生成并不意味着人脑发生了种子生成。我们认为，αSyn-SAA呈阳性表明存在病理性α-突触核蛋白，但不是单体α-突触核蛋白沉淀为其病理形式的潜在病因。因此，αSyn-SAA呈阳性支持PD的临床诊断，但不能为疾病发病机制提供信息，无法确定严重程度、预测进展速度、定义生物学特征或生物学亚型，也不能监测治疗反应。
