School of Psychology and Neuroscience, University of St Andrews, St Andrews, UK.
Edinburgh Super-Resolution Imaging Consortium, Heriot Watt University, Edinburgh, UK.
Acta Neuropathol. 2022 Apr;143(4):471-486. doi: 10.1007/s00401-022-02412-9. Epub 2022 Mar 19.
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Separate lines of evidence suggest that synapses and astrocytes play a role in the pathological mechanisms underlying ALS. Given that astrocytes make specialised contacts with some synapses, called tripartite synapses, we hypothesise that tripartite synapses could act as the fulcrum of disease in ALS. To test this hypothesis, we have performed an extensive microscopy-based investigation of synapses and tripartite synapses in the spinal cord of ALS model mice and post-mortem human tissue from ALS cases. We reveal widescale synaptic changes at the early symptomatic stages of the SOD1 mouse model. Super-resolution microscopy reveals that large complex postsynaptic structures are lost in ALS mice. Most surprisingly, tripartite synapses are selectively lost, while non-tripartite synapses remain in equal number to healthy controls. Finally, we also observe a similar selective loss of tripartite synapses in human post-mortem ALS spinal cords. From these data we conclude that tripartite synaptopathy is a key hallmark of ALS.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病。有证据表明，突触和星形胶质细胞在 ALS 的病理机制中起作用。鉴于星形胶质细胞与一些突触形成特殊的接触，称为三突触，我们假设三突触可能是 ALS 疾病的关键。为了验证这一假说，我们对 ALS 模型小鼠脊髓中的突触和三突触以及 ALS 病例的死后人类组织进行了广泛的显微镜检查。我们在 SOD1 小鼠模型的早期症状阶段揭示了广泛的突触变化。超分辨率显微镜显示，在 ALS 小鼠中，大而复杂的突触后结构丢失。最令人惊讶的是，三突触选择性丢失，而非三突触突触的数量与健康对照组相等。最后，我们还观察到在人类死后 ALS 脊髓中也存在类似的三突触选择性丢失。从这些数据中，我们得出结论，三突触病变是 ALS 的一个关键标志。
