An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD.
An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD.
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突触蛋白和 C9orf72 之间的相互作用调节兴奋性突触，并在 ALS/FTD 中受损。
DOI：
10.1007/s00401-022-02470-z
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发表时间：
2022-09
影响因子：
12.7
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中科院分区：
文献类型：
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突触功能障碍和退化是肌萎缩侧索硬化症和额颞叶痴呆（ALS/FTD）的共同特征。C9 ORF 72基因中的GGGGCC六核苷酸重复扩增是ALS/FTD（C9 ALS/FTD）的主要遗传原因。重复扩增导致C9 orf 72蛋白的表达减少。C9 orf 72单倍不足如何导致疾病尚未解决。在这里，我们确定了突触囊泡蛋白，最丰富的一组突触磷蛋白，作为新的相互作用的C9 orf 72在突触和显示，C9 orf 72在兴奋性突触的调节细胞自主的作用。我们将C9 orf 72和突触蛋白的相互作用定位到C9 orf 72的N端longin结构域和突触蛋白的保守C结构域，并显示了突触中内源性蛋白的相互作用。在功能上，C9 orf 72缺陷减少了兴奋性突触的数量，并在海马神经元体外培养和在体内C9 orf 72敲除小鼠的海马苔藓纤维系统中的剩余突触处降低突触蛋白水平。与突触功能障碍一致，电生理记录鉴定了海马神经元培养物中C9 orf 72表达降低的兴奋性神经传递和网络功能受损，这与C9 orf 72敲除小鼠海马中兴奋性突触的突触囊泡严重耗尽相关。最后，对C9 orf 72单倍不足的C9 ALS/FTD患者海马的尸检切片进行神经病理学分析，发现突触蛋白显著减少，表明C9 orf 72和突触蛋白之间相互作用的破坏可能导致ALS/FTD病理生物学。因此，我们的数据表明，C9 orf 72在兴奋性突触的神经传递的调节中起着细胞自主的作用，通过与突触蛋白的相互作用和突触囊泡池的调制，并确定C9 orf 72单倍不足在C9 ALS/FTD的突触功能障碍中的新作用。在线版本包含补充材料，可通过10.1007/s 00401 -022-02470-z获得。
Dysfunction and degeneration of synapses is a common feature of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene is the main genetic cause of ALS/FTD (C9ALS/FTD). The repeat expansion leads to reduced expression of the C9orf72 protein. How C9orf72 haploinsufficiency contributes to disease has not been resolved. Here we identify the synapsin family of synaptic vesicle proteins, the most abundant group of synaptic phosphoproteins, as novel interactors of C9orf72 at synapses and show that C9orf72 plays a cell-autonomous role in the regulation of excitatory synapses. We mapped the interaction of C9orf72 and synapsin to the N-terminal longin domain of C9orf72 and the conserved C domain of synapsin, and show interaction of the endogenous proteins in synapses. Functionally, C9orf72 deficiency reduced the number of excitatory synapses and decreased synapsin levels at remaining synapses in vitro in hippocampal neuron cultures and in vivo in the hippocampal mossy fibre system of C9orf72 knockout mice. Consistent with synaptic dysfunction, electrophysiological recordings identified impaired excitatory neurotransmission and network function in hippocampal neuron cultures with reduced C9orf72 expression, which correlated with a severe depletion of synaptic vesicles from excitatory synapses in the hippocampus of C9orf72 knockout mice. Finally, neuropathological analysis of post-mortem sections of C9ALS/FTD patient hippocampus with C9orf72 haploinsufficiency revealed a marked reduction in synapsin, indicating that disruption of the interaction between C9orf72 and synapsin may contribute to ALS/FTD pathobiology. Thus, our data show that C9orf72 plays a cell-autonomous role in the regulation of neurotransmission at excitatory synapses by interaction with synapsin and modulation of synaptic vesicle pools, and identify a novel role for C9orf72 haploinsufficiency in synaptic dysfunction in C9ALS/FTD. The online version contains supplementary material available at 10.1007/s00401-022-02470-z.