Department of Molecular and Cellular Biology, The University of Guelph, Guelph, ON, N1G 2W1, Canada.
Neurodegenerative Disease Center, Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, CA, 92121, USA.
Nat Commun. 2018 Feb 26;9(1):817. doi: 10.1038/s41467-018-03241-9.
Neuronal loss in Parkinson's disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Identifying the mechanisms that link these pathologies is critical to furthering our understanding of PD pathogenesis. Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding α-synuclein (α-syn)) with isogenic controls, or SNCA-transgenic mice, we show that SNCA-mutant neurons display fragmented mitochondria and accumulate α-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface. Whereas exposed cardiolipin specifically binds to and facilitates refolding of α-syn fibrils, prolonged cardiolipin exposure in SNCA-mutants initiates recruitment of LC3 to the mitochondria and mitophagy. Moreover, we find that co-culture of SNCA-mutant neurons with their isogenic controls results in transmission of α-syn pathology coincident with mitochondrial pathology in control neurons. Transmission of pathology is effectively blocked using an anti-α-syn monoclonal antibody (mAb), consistent with cell-to-cell seeding of α-syn.
帕金森病 (PD) 中的神经元丧失与异常的线粒体功能和蛋白质稳态受损有关。确定将这些病理学联系起来的机制对于深入了解 PD 的发病机制至关重要。使用允许比较表达突变 SNCA（编码 α-突触核蛋白 (α-syn)）的细胞与同基因对照或 SNCA 转基因小鼠的人多能干细胞 (hPSC)，我们表明 SNCA 突变神经元显示出线粒体碎片化，并在暴露于线粒体表面的心磷脂后积累 α-syn 沉积物，这些沉积物聚集在线粒体膜上。虽然暴露的心磷脂特异性结合并促进 α-syn 原纤维的重折叠，但 SNCA 突变体中的延长的心磷脂暴露会引发 LC3 向线粒体的募集和线粒体自噬。此外，我们发现 SNCA 突变神经元与同基因对照共培养会导致 α-syn 病理学与对照神经元中线粒体病理学同时传递。使用抗 α-syn 单克隆抗体 (mAb) 可有效阻断病理学的传递，这与 α-syn 的细胞间播种一致。
