Schuler Martin, Gerwert Grischa, Mann Marvin, Woitzik Nathalie, Langenhoff Lennart, Hubert Diana, Duman Deniz, Höveler Adrian, Galkowski Sandy, Simon Jonas, Denz Robin, Weber Sandrina, Kwon Eun-Hae, Wanka Robin, Kötting Carsten, Güldenhaupt Jörn, Beyer Léon, Tönges Lars, Mollenhauer Brit, Gerwert Klaus
Center for Protein Diagnostics (PRODI), Ruhr-University Bochum, Bochum, Germany.
Department of Biophysics, Ruhr-University Bochum, Bochum, Germany.
EMBO Mol Med. 2025 Apr 25. doi: 10.1038/s44321-025-00229-z.
Misfolding and aggregation of alpha-synuclein (αSyn) play a key role in the pathophysiology of Parkinson's disease (PD). Despite considerable advances in diagnostics, an early and differential diagnosis of PD still represents a major challenge. We innovated the immuno-infrared sensor (iRS) platform for measuring αSyn misfolding. We analyzed cerebrospinal fluid (CSF) from two cohorts comprising PD cases, atypical Parkinsonian disorders, and disease controls. We obtained an AUC of 0.90 (n = 134, 95% CI 0.85-0.96) for separating PD/MSA from controls by determination of the αSyn misfolding by iRS. Using two thresholds divided individuals as unaffected/affected by misfolding with an intermediate area in between. Comparing the affected/unaffected cases, controls versus PD/MSA cases were classified with 97% sensitivity and 92% specificity. The spectral data revealed misfolding from an α-helical/random-coil αSyn in controls to β-sheet enriched αSyn in PD and MSA cases. Moreover, a first subgroup analysis implied the potential for patient stratification in clinically overlapping cases. The iRS, directly measuring all αSyn conformers, is complementary to the αSyn seed-amplification assays (SAAs), which however only amplify seeding competent conformers.
α-突触核蛋白（αSyn）的错误折叠和聚集在帕金森病（PD）的病理生理学中起关键作用。尽管在诊断方面取得了相当大的进展，但PD的早期和鉴别诊断仍然是一项重大挑战。我们创新了用于测量αSyn错误折叠的免疫红外传感器（iRS）平台。我们分析了来自两个队列的脑脊液（CSF），这些队列包括PD病例、非典型帕金森氏症和疾病对照。通过iRS测定αSyn错误折叠，我们在区分PD/MSA与对照时获得了0.90的曲线下面积（AUC）（n = 134，95% CI 0.85 - 0.96）。使用两个阈值将个体分为未受错误折叠影响/受错误折叠影响，中间有一个中间区域。比较受影响/未受影响的病例，对照与PD/MSA病例的分类敏感性为97%，特异性为92%。光谱数据显示，从对照中α-螺旋/无规卷曲的αSyn到PD和MSA病例中富含β-折叠的αSyn发生了错误折叠。此外，首次亚组分析表明在临床重叠病例中进行患者分层具有潜力。iRS直接测量所有αSyn构象体，是αSyn种子扩增检测（SAA）的补充，然而SAA仅扩增具有种子形成能力的构象体。
