Tanz Centre for Research in Neurodegenerative Disease (CRND), University of Toronto, Krembil Discovery Tower, 60 Leonard Ave, Toronto, ON, M5T 0S8, Canada.
Edmond J. Safra Program in PD and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, ON, Canada.
Acta Neuropathol. 2022 Aug;144(2):167-185. doi: 10.1007/s00401-022-02453-0. Epub 2022 Jun 24.
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）的特征是错误折叠的α-突触核蛋白（α-Syn）的沉积，临床上具有异质性。尽管α-Syn 的分布与主要临床特征相关，但病理学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可变性。我们假设这种异质性可能反映了α-Syn 分子的多样性，无论是在患者之间还是不同的大脑区域之间。我们使用超灵敏的测定法，评估了 30 名具有不同临床表型和疾病持续时间的 LBD 患者的 8 个大脑区域中的α-Syn 播种情况。比较跨临床表型的播种情况表明，具有认知为主型表型的患者的海马α-Syn 具有显著更高的播种能力，而具有运动为主型表型的患者的黑质衍生α-Syn 又具有比认知为主型患者更高的播种能力。有趣的是，具有快速疾病进展（<3 年发展为晚期疾病）的患者的黑质α-Syn 具有所有患者中最高的播种能力。为了验证这些发现并探索播种异质性的基础，我们进行了体外毒性测定以及详细的神经病理学和生物化学检查。此外，我们还首次对 5 名高播种者和 5 名低播种者的黑质进行了蛋白质组学全面分析。蛋白质组学数据表明，与低播种者相比，高播种者的线粒体功能和脂质代谢明显受到干扰。这些观察结果表明，不同分子群体的α-Syn 可能导致 LBD 中的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，其不同影响的相对贡献解释了神经退行性过程中的异质性。
