Department of Molecular and Cellular Biology, The University of Guelph, Guelph, ON N1G 2W1, Canada.
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.
Cell Rep. 2021 May 11;35(6):109099. doi: 10.1016/j.celrep.2021.109099.
Neuronal loss in Parkinson's disease (PD) is associated with impaired proteostasis and accumulation of α-syn microaggregates in dopaminergic neurons. These microaggregates promote seeding of α-synuclein (α-syn) pathology between synaptically linked neurons. However, the mechanism by which seeding is initiated is not clear. Using human pluripotent stem cell (hPSC) models of PD that allow comparison of SNCA mutant cells with isogenic controls, we find that SNCA mutant neurons accumulate α-syn deposits that cluster to multiple endomembrane compartments, specifically multivesicular bodies (MVBs) and lysosomes. We demonstrate that A53T and E46K α-syn variants bind and sequester LC3B monomers into detergent-insoluble microaggregates on the surface of late endosomes, increasing α-syn excretion via exosomes and promoting seeding of α-syn from SNCA mutant neurons to wild-type (WT) isogenic controls. Finally, we show that constitutive inactivation of LC3B promotes α-syn accumulation and seeding, while LC3B activation inhibits these events, offering mechanistic insight into the spread of synucleinopathy in PD.
帕金森病（PD）中的神经元丧失与蛋白质稳态受损以及多巴胺能神经元中α-突触核蛋白（α-syn）微聚集体的积累有关。这些微聚集体促进了突触连接的神经元之间α-syn 病理学的播种。然而，引发播种的机制尚不清楚。我们使用允许比较 SNCA 突变细胞与同基因对照的 PD 人类多能干细胞（hPSC）模型，发现 SNCA 突变神经元积累了α-syn 沉积物，这些沉积物聚集到多个内质网隔室，特别是多泡体（MVB）和溶酶体。我们证明 A53T 和 E46K α-syn 变体结合并将 LC3B 单体隔离到晚期内体表面的去污剂不溶性微聚集体中，通过外泌体增加α-syn 的排泄，并促进 SNCA 突变神经元中α-syn 向野生型（WT）同基因对照的播种。最后，我们表明 LC3B 的组成性失活促进了α-syn 的积累和播种，而 LC3B 的激活抑制了这些事件，为 PD 中突触核蛋白病的传播提供了机制见解。
