Laboratory of Neuronal Cell Signaling, EBRI Rita Levi-Montalcini Foundation, Rome, Italy.
Department of Neurorehabilitation Sciences, Casa Cura Policlinico, Milan, Italy.
Mol Neurobiol. 2017 Oct;54(8):6609-6623. doi: 10.1007/s12035-016-0176-9. Epub 2016 Oct 13.
Synaptic dysfunction has been recognized as an early feature occurring at the onset of Alzheimer's disease (AD). Compromised neurotransmission leads over time to synaptic loss and these events correlate with the cognitive decline that progressively affects AD patients.Protein SUMOylation (Small Ubiquitin-like MOdifier) is a post-translational modification (PTM) involved in several cellular processes including synaptic transmission.We here demonstrate that cortical synaptosomes prepared from Tg2576 mice of 6 months of age show an increased SUMO-1ylation, which returns back to normal levels at 20 months although synaptic SUMOylation, at this age, resulted more sensible to KCl stimulus. Our previous findings have shown that increased SUMOylation at presynaptic level reduces the KCl-induced glutamate release. Accordingly, Tg2576 mice of 6 and 20 months show a reduced KCl-evoked neurotransmitter (NT) release. In order to target SUMOylation, we developed two cell penetrating HIV Tat-linked peptides, namely TU-1 and TS-1. This strategy allowed us to modulate the SUMO machinery either positively (TU-1) or negatively (TS-1). As expected, Tg2576 synaptosomes treated with TU-1 exhibited a reduced NT release evoked by KCl. On the contrary, TS-1 treatment, which decreased SUMOylation, was able to normalize impaired glutamate release. Notably, an analysis of autopsy human AD brains has shown an increased SUMOylation in both cortical tissue and synaptosomal lysate. Our data indicate that SUMOylation level changes contribute to the development of synaptic alterations typically occurring at the AD onset and that SUMOylation could be a pharmacological target in AD synaptic dysfunction.
突触功能障碍已被认为是阿尔茨海默病（AD）发病时的早期特征。随着时间的推移，神经传递受损会导致突触丧失，这些事件与逐渐影响 AD 患者的认知能力下降相关。蛋白质 SUMOylation（小泛素样修饰物）是一种参与包括突触传递在内的多种细胞过程的翻译后修饰（PTM）。我们在此证明，来自 6 个月大的 Tg2576 小鼠的皮质突触体显示出 SUMO-1 化的增加，尽管在此年龄，突触 SUMOylation 对 KCl 刺激更加敏感，但在 20 个月时恢复到正常水平。我们之前的研究结果表明，突触前水平的 SUMOylation 增加会减少 KCl 诱导的谷氨酸释放。因此，6 个月和 20 个月大的 Tg2576 小鼠表现出 KCl 诱发的神经递质（NT）释放减少。为了靶向 SUMOylation，我们开发了两种穿透细胞的 HIV Tat 连接肽，即 TU-1 和 TS-1。这种策略使我们能够正向（TU-1）或负向（TS-1）调节 SUMO 机器。正如预期的那样，用 TU-1 处理的 Tg2576 突触体表现出由 KCl 引起的 NT 释放减少。相反，TS-1 处理可降低 SUMOylation，从而使谷氨酸释放受损正常化。值得注意的是，对 AD 人脑尸检的分析表明，皮质组织和突触体裂解物中的 SUMOylation 均增加。我们的数据表明，SUMOylation 水平的变化有助于发生在 AD 发病时的突触改变的发展，并且 SUMOylation 可能是 AD 突触功能障碍的药理学靶点。
