Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Nautical Medicine, Academy of Special Environmental Medicine, Nantong University, Nantong 226001, China.
Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China.
Cell Rep. 2019 Jul 23;28(4):1015-1028.e5. doi: 10.1016/j.celrep.2019.06.006.
Presynaptic endosomes reportedly participate in synaptic vesicle (SV) recycling. However, it remains unclear whether they differentially regulate SV biogenesis and synaptic transmission in different types of synapses and how they are implicated in diseases. Using cryo-electron tomography and endocytic tracing, we uncover different endocytic modes and dynamics associated with distinct SV morphology between glutamatergic and GABAergic synapses. We further find that cathepsin D (CatD), a lysosomal storage disease (LSD) protein, is selectively located in GABAergic presynaptic endosomes. Inactivation of CatD results in enlarged presynaptic endosomes, reduces the readily releasable pool, and impairs synaptic transmission in GABAergic, but not glutamatergic, synapses. Moreover, CatD-deficient mice exhibit hyperactivity and increased sensitivity to seizure, mimicking epileptic behavior in CatD-related LSD patients. These data reveal an important role for presynaptic endosomal CatD in regulating GABAergic SV biogenesis and provide mechanistic insights for understanding the synaptic pathology and behavioral defects in CatD-associated LSD.
据报道，突触前内体参与突触小泡（SV）的再循环。然而，目前尚不清楚它们是否在不同类型的突触中差异调节 SV 的生物发生和突触传递，以及它们如何与疾病相关。我们使用冷冻电子断层扫描和内吞追踪技术，揭示了谷氨酸能和 GABA 能突触之间与不同 SV 形态相关的不同内吞模式和动力学。我们进一步发现，组织蛋白酶 D（CatD），一种溶酶体贮积病（LSD）蛋白，选择性地位于 GABA 能突触前内体中。CatD 的失活导致突触前内体增大，可释放池减少，并损害 GABA 能，但不损害谷氨酸能突触的传递。此外，CatD 缺陷小鼠表现出过度活跃和对癫痫发作的敏感性增加，模拟了与 CatD 相关的 LSD 患者的癫痫行为。这些数据揭示了突触前内体 CatD 在调节 GABA 能 SV 生物发生中的重要作用，并为理解 CatD 相关 LSD 的突触病理学和行为缺陷提供了机制见解。
