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An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD.
Bauer, Claudia S; Cohen, Rebecca N; Sironi, Francesca; Livesey, Matthew R; Gillingwater, Thomas H; Highley, J Robin; Fillingham, Daniel J; Coldicott, Ian; Smith, Emma F; Gibson, Yolanda B; Webster, Christopher P; Grierson, Andrew J; Bendotti, Caterina; De Vos, Kurt J.
Afiliação
  • Bauer CS; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
  • Cohen RN; Neuroscience Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
  • Sironi F; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
  • Livesey MR; Neuroscience Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
  • Gillingwater TH; Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy.
  • Highley JR; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
  • Fillingham DJ; Neuroscience Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
  • Coldicott I; Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Hugh Robson Building, Edinburgh, EH8 9XD, UK.
  • Smith EF; Euan MacDonald Centre for Motor Neuron Disease Research, Chancellor's Building, University of Edinburgh, Edinburgh, EH16 4SB, UK.
  • Gibson YB; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
  • Webster CP; Neuroscience Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
  • Grierson AJ; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
  • Bendotti C; Neuroscience Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
  • De Vos KJ; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
Acta Neuropathol ; 144(3): 437-464, 2022 09.
Article em En | MEDLINE | ID: mdl-35876881
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sinapsinas / Demência Frontotemporal / Proteína C9orf72 / Esclerose Lateral Amiotrófica Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sinapsinas / Demência Frontotemporal / Proteína C9orf72 / Esclerose Lateral Amiotrófica Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article