Aug 2026· Cell Reports· Vol 45 8, pp.
117827
· 0 citations· 54 references
Medicine
TL;DR
Affinity purification-based proteomics shows that Ptn associates with heparan sulfate (HS)-modified neurexin1 (HS-Nrxn1) in the brain through an HS-glycan-dependent mechanism, which establishes Ptn as an extracellular organizer of presynaptic development and support a model in which Nrxn1's HS glycan provides a platform for extracellular ligand recruitment.
Abstract
Synapses are the fundamental units of neural circuits, and their dysfunction contributes to numerous neuropsychiatric disorders. Although synaptic adhesion proteins have been well studied, how extracellular cues and matrix glycans specify synaptic properties remains much less well understood. Here, we identify pleiotrophin (Ptn) as a regulator of presynaptic development. Affinity purification-based proteomics shows that Ptn associates with heparan sulfate (HS)-modified neurexin1 (HS-Nrxn1) in the brain through an HS-glycan-dependent mechanism. Glycan microarray analyses further reveal that Ptn selectively recognizes defined HS sulfation motifs. Functionally, Ptn requires both HS glycans and Nrxns to induce presynaptic assembly in cultured neurons. In vivo, Ptn deletion disrupts presynaptic protein clustering, reduces neurotransmitter release probability at CA3-CA1 synapses, and impairs contextual fear discrimination. Together, these findings establish Ptn as an extracellular organizer of presynaptic development and support a model in which Nrxn1's HS glycan provides a platform for extracellular ligand recruitment.
Synapses, prototypic sites for neuronal communication, are key to brain function. Their organization and properties are instructed by synaptic cell adhesion molecules (sCAMs) that may operate independently or in coordination through yet unknown linker proteins. Here, we used multi-epitope affinity-purifications combined with quantitative mass spectrometry and immuno-EM to comprehensively map synaptic protein networks in the mouse brain. We identify a pre-synaptic core-module assembled from the major sCAMs, Neurexins1-3 and LAR-type receptor protein-tyrosine-phosphatases (PTPRs), and the previously uncharacterized tetraspanins T178A/B. These ternary Neurexin-T178-PTPR complexes form through their trans-membrane domains and assemble during biogenesis in the ER. Loss of T178B leads to module destabilization, accompanied by strong reduction of LAR-PTPRs and re-distribution of synaptic Neurexins. At synapses, the Neurexin-T178-PTPR module recruits stable trans-synaptic protein networks thereby interlinking machineries of the pre-synaptic active zone and establishing stable associations with post-synaptic neurotransmitter receptors. This work uncovers a widely distributed core-module for synaptic adhesion and trans-synaptic signaling in the mammalian brain. Organization and function of CNS synapses are instructed by synaptic cell adhesion molecules (sCAM). Here, authors show that the main sCAMs NRX and PTPRs are interlinked by the tetraspanins T178A,B, thus forming ternary complexes that serve as core-modules of transsynaptic networks.
Gephyrin is identified as the primary synaptic anchor for PX-RICS and the N-terminal gephyrin-binding region (GBR) engages gephyrin E-domain through conserved hydrophobic interactions, explaining the isoform-specific targeting of PX-RICS (but not RICS) to inhibitory synapses.
Guanhua Bai, Ruifeng Huang, Yinmiao Lian et al.· Proceedings of the National...· 0 citations
Persistent synaptic plasticity is essential for memory, yet its stabilizing mechanisms remain incompletely understood. AMPA-type glutamate receptors (AMPARs) mediate most fast excitatory transmission in the brain, but how extracellular posttranslational modifications regulate their functional dynamics in vivo remains unclear. Here, we identify a single endogenous N-linked glycan at Asn401 of the AMPAR GluA1 subunit as a regulator that links receptor gating, membrane microdomain organization, and memory persistence. Loss of this glycan markedly reduced AMPAR desensitization and promoted resensitization. Biochemical and imaging analyses showed that GluA1 lacking the N401 glycan preferentially partitions into ganglioside-rich lipid raft microdomains through enhanced ganglioside binding, thereby disrupting activity-dependent receptor trafficking and promoting excessive receptor internalization. Using GluA1 N401Q knock-in mice, we show that loss of this glycan selectively impairs hippocampal long-term potentiation maintenance and compromises contextual and spatial memory persistence, while leaving learning acquisition largely intact. Notably, this site exhibits partial occupancy in the mammalian brain, indicating that it functions as an endogenous tunable constraint on synaptic stability. Together, these findings establish site-specific glycosylation as a mechanism that coordinates AMPAR gating with membrane compartmentalization to control persistent synaptic plasticity and memory in vivo.
R. Midorikawa, Yoshihiko Wakazono, Sunita K. C. Basnet et al.· Proceedings of the National...· 0 citations
As a key component of the cytoskeleton, microtubule dynamics provide structural support for neurite growth. Spastin plays a critical role in reshaping microtubule arrangement, which is essential for axon development and regeneration. However, the mechanism by which spastin is activated and functions remains unclear. In this study, we discovered that phosphorylation of spastin at Ser210 promotes dendrite growth and surface expression of GluA1 in neurons, enhancing synaptic transmission. Conversely, dephosphorylation of spastin inhibits dendrite growth and surface expression of GluA1, weakening synaptic transmission. PTEN interacts with the MIT domain of spastin through its C-terminal region, resulting in reduced spastin phosphorylation expression levels. This process suppresses the transport of the AMPA receptor GluA1 subunit, thereby modulating neurite outgrowth and weakening synaptic transmission. In conclusion, our research indicates that PTEN is the pathway that regulates the phosphorylation of spastin, providing an important reference for the treatment of neurological diseases characterized by microtubule dysregulation.
Danlei Liu, Jiagui Zhong, Laijian Wang et al.· ACS Chemical Neuroscience· 0 citations
Group III metabotropic glutamate receptors (mGluRs) are critical signaling molecules that regulate strength, homeostasis, and plasticity of glutamatergic synaptic signaling. These receptors are engaged in transsynaptic interactions with extracellular leucine-rich repeat and fibronectin type III domain-containing (ELFN) cell adhesion proteins. ELFN proteins have been shown to play a critical role in regulation of activity and localization of mGluRs activity in vivo, yet the exact nature of their regulatory interaction has remained unknown. Here, we present a cryo-electron microscopy structure of the ELFN-mGluR complex. We identify a specific ELFN-binding pocket on mGluRs involved in its allosteric regulation through the network of residues affecting the orthosteric ligand binding site. We further uncover cooperativity whereby mGluR activation increases their association with ELFN proteins as a potential feedback mechanism to regulate synaptic strength. Last, we determine that disruption in mGluR-ELFN interaction is a recurring mechanism underlying several neurological conditions as we delineate their structure-functional etiology.
How LRRK2-dependent trafficking mechanisms regulate key components of synaptic transmission, including glutamatergic and GABAergic receptors, as well as astrocytic transporters are examined, highlighting how disruption of these processes affects neurotransmitter clearance, receptor activation, and ultimately E/I balance.
Angela Di Iacovo, Chiara D’Agostino, Giulia Casoli et al.· Cellular and molecular neuro...· 0 citations
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