@article{7a919e9a5785448eab46e2e41661dc05,
title = "An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD",
abstract = "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.",
keywords = "C9orf72, amyotrophic lateral sclerosis, frontotemporal dementia, synapsin, synapse",
author = "Bauer, {Claudia S} and Cohen, {Rebecca N} and Francesca Sironi and Livesey, {Matthew R} and Gillingwater, {Thomas H} and Highley, {J Robin} and Fillingham, {Daniel J} and Ian Coldicott and Smith, {Emma F} and Gibson, {Yolanda B} and Webster, {Christopher P} and Grierson, {Andrew J} and Caterina Bendotti and {De Vos}, {Kurt J}",
note = "Funding Information: We thank Dr. Daniel Gitler, Ben-Gurion University, Israel for sharing synapsin reagents. We are grateful to the Sheffield Brain Tissue Bank and the very generous individuals who have donated tissue for this research and the next of kin who have accommodated this. The authors thank Steve Mitchell for technical assistance with electron microscopy and the technical and administrative team in SITraN for supporting our work. This work was funded by an Alzheimer{\textquoteright}s Research UK project grant (ARUK-PG2019A-008 to KJDV) with additional support from the Medical Research Council (MRC) (MR/S025979/1 and MR/M013251/1 to KJDV) and by Regione Lombardia, Italy, “POR FESR 2014–2020 resources Call HUB Ricerca Innovazione” (CB, FS). EFS was supported by the Motor Neurone Disease Association (DEVOS/APR18/862-791 to KJDV and AJG). RNC was supported by a University of Sheffield Prize studentship. The Y2H screen was funded by the Thierry Latran Foundation (project RoCIP to KJDV and AJG). Funding Information: We thank Dr. Daniel Gitler, Ben-Gurion University, Israel for sharing synapsin reagents. We are grateful to the Sheffield Brain Tissue Bank and the very generous individuals who have donated tissue for this research and the next of kin who have accommodated this. The authors thank Steve Mitchell for technical assistance with electron microscopy and the technical and administrative team in SITraN for supporting our work. This work was funded by an Alzheimer{\textquoteright}s Research UK project grant (ARUK-PG2019A-008 to KJDV) with additional support from the Medical Research Council (MRC) (MR/S025979/1 and MR/M013251/1 to KJDV) and by Regione Lombardia, Italy, “POR FESR 2014–2020 resources Call HUB Ricerca Innovazione” (CB, FS). EFS was supported by the Motor Neurone Disease Association (DEVOS/APR18/862-791 to KJDV and AJG). RNC was supported by a University of Sheffield Prize studentship. The Y2H screen was funded by the Thierry Latran Foundation (project RoCIP to KJDV and AJG). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = sep,
language = "English",
volume = "144",
pages = "437–464",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer",
}