An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD

被引:20
作者
Bauer, Claudia S. [1 ,2 ]
Cohen, Rebecca N. [1 ,2 ]
Sironi, Francesca [3 ]
Livesey, Matthew R. [1 ,2 ]
Gillingwater, Thomas H. [4 ,5 ]
Highley, J. Robin [1 ,2 ]
Fillingham, Daniel J. [1 ,2 ]
Coldicott, Ian [1 ,2 ]
Smith, Emma F. [1 ,2 ]
Gibson, Yolanda B. [1 ,2 ]
Webster, Christopher P. [1 ,2 ]
Grierson, Andrew J. [1 ,2 ]
Bendotti, Caterina [3 ]
De Vos, Kurt J. [1 ,2 ]
机构
[1] Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, Dept Neurosci, 385a Glossop Rd, Sheffield S10 2HQ, S Yorkshire, England
[2] Univ Sheffield, Neurosci Inst, Sheffield S10 2TN, S Yorkshire, England
[3] Ist Ric Farmacol Mario Negri IRCCS, Lab Mol Neurobiol, Dept Neurosci, Via Mario Negri 2, I-20156 Milan, Italy
[4] Univ Edinburgh, Edinburgh Med Sch Biomed Sci, Hugh Robson Bldg, Edinburgh EH8 9XD, Midlothian, Scotland
[5] Univ Edinburgh, Euan MacDonald Ctr Motor Neuron Dis Res, Chancellors Bldg, Edinburgh EH16 4SB, Midlothian, Scotland
基金
英国医学研究理事会;
关键词
C9orf72; Amyotrophic lateral sclerosis; Frontotemporal dementia; Synapsin; Synapse; AMYOTROPHIC-LATERAL-SCLEROSIS; HEXANUCLEOTIDE REPEAT EXPANSION; SMALL SYNAPTIC VESICLES; RAB3 EFFECTOR PROTEIN; FRONTOTEMPORAL DEMENTIA; GENE-EXPRESSION; PATHOLOGY; MUTATION; BRAIN; MICE;
D O I
10.1007/s00401-022-02470-z
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:437 / 464
页数:28
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