Center of Health Management and Department of General Medicine, Daping Hospital, Army Medical University(Third Military Medical University), Chongqing 400042, China.
Department of Neurology, the Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China.
Neurosci Lett. 2022 Aug 10;785:136771. doi: 10.1016/j.neulet.2022.136771. Epub 2022 Jul 2.
Ubiquitin conjugating enzyme 9 (UBC9), the sole small ubiquitin-like modifier(SUMO) conjugating enzyme, is considered to be a vital regulator of the mechanism of SUMOylation and is likely to participate in the progression of Alzheimer's disease (AD). Our previous studies found that UBC9 is highly mobile in neurons, but the underlying mechanism is still unknown. We designed to investigate the underlying mechanism of the synaptic redistribution of UBC9 in AD. We found that β-amyloid peptide (Aβ) significantly decreased presynaptic UBC9 expression and increased postsynaptic UBC9 expression but did not affect UBC9 expression in synaptosomes. Moreover, there is evidence that extracellular vesicles (EVs) may facilitate synaptic gap transmission. Immunoprecipitation assays showed that flotillin, which is specifically expressed in EVs, co-immunoprecipitated with UBC9 in cell lysates and media and that Aβ treatment enhanced this interaction. Additionally, epidermal growth factor and oleanolic acid have been found to either promote or inhibit the release of EVs, thus blocking the Aβ-induced presynaptic release of UBC9. However, knockdown of synaptosome associated protein 23 (SNAP-23) or inhibition of SNAP23 phosphorylation was found to secure Aβ-induced presynaptic release of UBC9. These results suggest that Aβ induces redistribution of UBC9 from presynaptic to postsynaptic terminals, which may mediate through EVs associated with SNAP23. Our study reveals the cellular mechanisms of EVs as an essential component of the presynaptic release of UBC9.
泛素连接酶 9（UBC9）是唯一的小泛素样修饰物（SUMO）连接酶，被认为是 SUMOylation 机制的重要调节剂，可能参与阿尔茨海默病（AD）的进展。我们之前的研究发现 UBC9 在神经元中具有高度的流动性，但潜在的机制尚不清楚。我们旨在研究 AD 中 UBC9 突触重新分布的潜在机制。我们发现β-淀粉样肽（Aβ）显著降低了突触前 UBC9 的表达，增加了突触后 UBC9 的表达，但对突触体中的 UBC9 表达没有影响。此外，有证据表明细胞外囊泡（EVs）可能促进突触间隙传递。免疫沉淀测定表明，专门在 EVs 中表达的 flotillin 在细胞裂解物和培养基中与 UBC9 共免疫沉淀，并且 Aβ 处理增强了这种相互作用。此外，已经发现表皮生长因子和齐墩果酸要么促进要么抑制 EVs 的释放，从而阻断 Aβ 诱导的 UBC9 突触前释放。然而，发现突触相关蛋白 23（SNAP-23）的敲低或 SNAP23 磷酸化的抑制可确保 Aβ 诱导的 UBC9 突触前释放。这些结果表明，Aβ 诱导 UBC9 从突触前到突触后末端重新分布，这可能通过与 SNAP23 相关的 EV 介导。我们的研究揭示了 EVs 作为 UBC9 突触前释放的重要组成部分的细胞机制。
