Dynamic extracellular interactions with AMPA receptors
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Rattus Sp. (ncbitaxon:10118)
SUBMITTER: 
Richard L. Huganir
PROVIDER: MSV000099578 | MassIVE | Thu Oct 23 18:06:00 BST 2025
REPOSITORIES: MassIVE
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Project description: Not available
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Project description:FUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNA, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages. Despite apparently unaltered synaptic organization, RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS relocalization to the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration.
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Project description:FUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNA, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages. Despite apparently unaltered synaptic organization, RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS relocalization to the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration.
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Project description:Synapses are highly dynamic during early brain development, enabling the rapid adaptations that occur as neural circuits remodel in response to experience. The extracellular matrix (ECM) has been proposed as a critical regulator of synaptic plasticity in the brain. However, the molecular mechanisms that regulate the ECM and their impact on structural plasticity of synapses during brain development are unknown. Here, using time lapse imaging of excitatory synapses in zebrafish hindbrain motor neurons during development we observed synapses that were both short lived (<6 hours), and longer lived (>24 hours). Loss of ECM via hyaluronidase digestion or genetic deletion of brevican preferentially destabilized short-lived synapses relative to stable synapses, leading to increased synapse density. Conversely, genetic loss of matrix metalloprotease 14 (MMP14) led to accumulation of brevican and stabilized short-lived synapses, resulting in increased synapse density. Zebrafish microglial processes contacted synapses and expressed cell surface MMP14. Microglial MMP14 was required for its effects on synapse numbers and brevican digestion both in zebrafish as well as in triculture from human induced pluripotent stem cells. These pathways also impacted motor habituation in freely swimming fish and were required for stress-induced synapse plasticity. Based on these findings, we propose a model whereby ECM accumulation during development increases the probability that a synapse will convert from dynamic to stable. These studies define a molecular mechanism whereby ECM remodeling by microglia promote synapse plasticity in the developing brain.
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