ArticleActa neuropathologica2022
An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD.
Article in Acta neuropathologica, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 35 citations in OpenAlex.
- Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage.Molecular psychiatry · 2026Article
- Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration inInternational journal of molecular sciences · 2026Article
- Synaptic aging and neurodegeneration: the role of synaptic vesicle dynamics and neurotransmitter imbalance.Biogerontology · 2026Review
- γ-Radiation induces region-specific subcellular alterations of amyotrophic lateral sclerosis and frontotemporal dementia markers in swine brain.Scientific reports · 2026Article
- Microglial Extracellular Vesicles Mediate C1q Deposition at the Pre-Synapse and Promote Synaptic Pruning.Journal of extracellular vesicles · 2025Article
- Loss of C9orf72 impacts the peripheral neuromuscular system via immune dysregulation and accelerates the progression of amyotrophic lateral sclerosis in SOD-1 mutant mice.Journal of neuroinflammation · 2025Article
- Article
- Neuronal activity-dependent gene dysregulation inAmerican journal of physiology. Cell physiology · 2025Article
- Synapse vulnerability and resilience across the clinical spectrum of dementias.Nature reviews. Neurology · 2025Review
- RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD.Life science alliance · 2025Article
- Machine learning identified novel players in lipid metabolism, endosomal trafficking, and iron metabolism of the ALS spinal cord.Scientific reports · 2025Article
- Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.Acta neuropathologica communications · 2024Article
- Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances.International journal of molecular sciences · 2024Review
- Article
- Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis.Brain : a journal of neurology · 2024Review
- How do we get from hyperexcitability to excitotoxicity in amyotrophic lateral sclerosis?Brain : a journal of neurology · 2024Review
- Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD.Nature communications · 2023Article
- Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.Neurology and therapy · 2023Article
- Multiomics and machine-learning identify novel transcriptional and mutational signatures in amyotrophic lateral sclerosis.Brain : a journal of neurology · 2023Article
- Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS.Acta neuropathologica · 2023Article
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.