Lewy body disorders (LBD), characterized by the deposition of misfolded α-synuclein (α-Syn), are clinically heterogeneous. Although the distribution of α-Syn correlates with the predominant clinical features, the burden of pathology does not fully explain the observed variability in clinical presentation and rate of disease progression. We hypothesized that this heterogeneity might reflect α-Syn molecular diversity, between both patients and different brain regions. Using an ultra-sensitive assay, we evaluated α-Syn seeding in 8 brain regions from 30 LBD patients with different clinical phenotypes and disease durations. Comparing seeding across the clinical phenotypes revealed that hippocampal α-Syn from patients with a cognitive-predominant phenotype had significantly higher seeding capacity than that derived from patients with a motor-predominant phenotype, whose nigral-derived α-Syn in turn had higher seeding capacity than that from cognitive-predominant patients. Interestingly, α-Syn from patients with rapid disease progression (< 3 years to development of advanced disease) had the highest nigral seeding capacity of all the patients included. To validate these findings and explore factors underlying seeding heterogeneity, we performed in vitro toxicity assays, and detailed neuropathological and biochemical examinations. Furthermore, and for the first time, we performed a proteomic-wide profiling of the substantia nigra from 5 high seeder and 5 low seeder patients. The proteomic data suggests a significant disruption in mitochondrial function and lipid metabolism in high seeder cases compared to the low seeders. These observations suggest that distinct molecular populations of α-Syn may contribute to heterogeneity in phenotypes and progression rates in LBD and imply that effective therapeutic strategies might need to be directed at an ensemble of differently misfolded α-Syn species, with the relative contribution of their differing impacts accounting for heterogeneity in the neurodegenerative process.

路易体病 (LBD) 以错误折叠的 α-突触核蛋白 (α-Syn) 沉积为特征，在临床上存在异质性。尽管 α-Syn 的分布与主要临床特征相关，但病理负担并不能完全解释观察到的临床表现和疾病进展速度的变异性。我们假设这种异质性可能反映了患者和不同大脑区域之间的 α-Syn 分子多样性。使用超灵敏测定法，我们评估了来自 30 名具有不同临床表型和疾病持续时间的 LBD 患者的 8 个脑区中的 α-Syn 播种。比较临床表型的播种显示，来自具有认知主导表型的患者的海马 α-Syn 的播种能力明显高于来自具有运动主导表型的患者的海马 α-Syn，后者的黑质衍生 α-Syn 反过来具有更高的播种能力高于认知优势患者。有趣的是，来自疾病快速进展（< 3 年发展为晚期疾病）患者的 α-Syn 在所有患者中具有最高的黑质播种能力。为了验证这些发现并探索播种异质性的潜在因素，我们进行了体外毒性测定，并进行了详细的神经病理学和生化检查。此外，也是第一次，我们对来自 5 名高播种者和 5 名低播种者患者的黑质进行了蛋白质组学范围的分析。蛋白质组学数据表明，与低播种者相比，高播种者病例的线粒体功能和脂质代谢发生显着破坏。这些观察结果表明，不同的 α-Syn 分子群可能导致 LBD 表型和进展率的异质性，并暗示有效的治疗策略可能需要针对不同错误折叠的 α-Syn 物种的集合，以及它们的相对贡献不同的影响解释了神经退行性过程中的异质性。