Department of Neurology, New York, NY, USA; Center for Motor Neuron Biology & Disease, New York, NY, USA.
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Neuron. 2023 May 3;111(9):1423-1439.e4. doi: 10.1016/j.neuron.2023.02.004. Epub 2023 Mar 1.
Reduced survival motor neuron (SMN) protein triggers the motor neuron disease, spinal muscular atrophy (SMA). Restoring SMN prevents disease, but it is not known how neuromuscular function is preserved. We used model mice to map and identify an Hspa8 synaptic chaperone variant, which suppressed SMA. Expression of the variant in the severely affected mutant mice increased lifespan >10-fold, improved motor performance, and mitigated neuromuscular pathology. Mechanistically, Hspa8 altered SMN2 splicing and simultaneously stimulated formation of a tripartite chaperone complex, critical for synaptic homeostasis, by augmenting its interaction with other complex members. Concomitantly, synaptic vesicular SNARE complex formation, which relies on chaperone activity for sustained neuromuscular synaptic transmission, was found perturbed in SMA mice and patient-derived motor neurons and was restored in modified mutants. Identification of the Hspa8 SMA modifier implicates SMN in SNARE complex assembly and casts new light on how deficiency of the ubiquitous protein causes motor neuron disease.
运动神经元存活数减少（SMN）蛋白触发运动神经元疾病，脊髓性肌萎缩症（SMA）。恢复 SMN 可以预防疾病，但尚不清楚如何保持神经肌肉功能。我们使用模型小鼠来绘制和鉴定 HSPA8 突触伴侣变体，它可以抑制 SMA。在严重受影响的突变小鼠中表达该变体可使寿命延长 10 倍以上，改善运动性能并减轻神经肌肉病理。从机制上讲，HSPA8 改变了 SMN2 的剪接，并通过增强其与其他复合物成员的相互作用，同时刺激形成了对突触稳态至关重要的三组分伴侣复合物。同时，在 SMA 小鼠和源自患者的运动神经元中发现，依赖伴侣活性进行持续的神经肌肉突触传递的突触小泡 SNARE 复合物形成受到干扰，并且在改良的突变体中得到恢复。HSPA8 SMA 调节剂的鉴定提示 SMN 参与 SNARE 复合物的组装，并为普遍存在的蛋白质缺乏如何导致运动神经元疾病提供了新的认识。
