Pons Marie-Laure, Mohaupt Pablo, Vialaret Jérôme, Mondesert Etienne, Vignon Margaux, Coppens Salomé, Stéphane Moreau, Lehmann Sylvain, Hirtz Christophe
LBPC-PPC, Université de Montpellier, IRMB CHU de Montpellier, INM INSERM, Montpellier 34295, France.
Shimadzu Corporation, LC-MS & Life Sciences, Duisburg 47269, Germany.
Brain Commun. 2025 May 20;7(3):fcaf189. doi: 10.1093/braincomms/fcaf189. eCollection 2025.
The differential diagnosis of α-synucleinopathies, including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), remains challenging due to overlapping clinical features and the absence of reliable biomarkers. We developed a targeted mass spectrometry assay to profile α-synuclein peptides in plasma from Parkinson's disease ( = 82), DLB ( = 32), MSA ( = 8) and controls ( = 21). We hypothesized that disease-specific truncations or post-translational modifications would alter levels of non-modified α-synuclein peptides across α-synucleinopathies. The assay quantified non-modified peptides derived from the N-terminus and non-amyloid component (NAC) domain, regions implicated in aggregate formation. Although peptide levels were consistent across disease groups, a distinct NAC domain pattern observed in MSA may reflect unique pathological processes. This study presents the first blood-based profiling of α-synuclein peptides in these disorders, offering a basis for further investigation into disease mechanisms. Refinement of the assay to include post-translational modifications could enhance understanding of α-synucleinopathies and support future biomarker development.
α-突触核蛋白病的鉴别诊断颇具挑战，其中包括帕金森病、路易体痴呆（DLB）和多系统萎缩（MSA），原因在于临床特征重叠且缺乏可靠的生物标志物。我们开发了一种靶向质谱分析法，用于分析帕金森病（n = 82）、DLB（n = 32）、MSA（n = 8）患者及对照者（n = 21）血浆中的α-突触核蛋白肽。我们推测，疾病特异性的截断或翻译后修饰会改变不同α-突触核蛋白病中非修饰α-突触核蛋白肽的水平。该分析方法对源自N端和非淀粉样成分（NAC）结构域（与聚集体形成有关的区域）的非修饰肽进行了定量。尽管各疾病组的肽水平一致，但在MSA中观察到的独特NAC结构域模式可能反映了独特的病理过程。本研究首次对这些疾病中的α-突触核蛋白肽进行了基于血液的分析，为进一步研究疾病机制提供了基础。完善该分析方法以纳入翻译后修饰，可能会增进对α-突触核蛋白病的理解，并支持未来生物标志物的开发。
