The endosomal protein sorting nexin 4 is a synaptic protein

Vázquez-Sánchez, Sonia; Gonzalez‐Lozano, Miguel A.; Walfenzao, Alexarae; Li, Ka Wan; Weering, Jan R.T. van

doi:10.1038/s41598-020-74694-6

Cited by 14 publications

(9 citation statements)

References 33 publications

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“…In total, the hippocampal P2 fraction of SH-WT and SH-RX mice revealed 12 and 9 altered gene products, respectively, that were already altered in the hippocampal fraction of Tg Camk2a-tTA mice (Tables S1 – S3 ). From the remaining 20 SH-WT and SH-RX gene products with different P2 levels in hippocampi, 6 proteins were detected by using only a single peptide in the MS and might need further validation [ 24 ]. Notably, from those 20 proteins, 13 proteins are involved in axonal or neurodevelopmental functions and only 7 also in postsynaptic function, whereas the contribution of differentially changed postsynaptic proteins in the P2 fraction was much more pronounced in SH-WT mice.…”

Section: Resultsmentioning

confidence: 99%

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

et al. 2021

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Mutations in SHANK genes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported in Shank KO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK proteins, but these remain poorly defined. In this study, we examined how SHANK2 can mediate electrophysiological, molecular, and behavioral effects by conditionally overexpressing either wild-type SHANK2A or the extrasynaptic SHANK2A(R462X) variant. SHANK2A overexpression affected pre- and postsynaptic targets and revealed a reversible, development-dependent autism spectrum disorder-like behavior. SHANK2A also mediated redistribution of Ca2+-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, leading to impaired synaptic plasticity in the basal dendrites. Moreover, SHANK2A overexpression reduced social interaction and increased the excitatory noise in the olfactory cortex during odor processing. In contrast, overexpression of the extrasynaptic SHANK2A(R462X) variant did not impair hippocampal synaptic plasticity, but still altered the expression of presynaptic/axonal signaling proteins. We also observed an attention-deficit/hyperactivity-like behavior and improved social interaction along with enhanced signal-to-noise ratio in cortical odor processing. Our results suggest that the disruption of pre- and postsynaptic SHANK2 functions caused by SHANK2 mutations has a strong impact on social behavior. These findings indicate that pre- and postsynaptic SHANK2 actions cooperate for normal neuronal function, and that an imbalance between these functions may lead to different neuropsychiatric disorders.

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Section: Resultsmentioning

confidence: 99%

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

et al. 2021

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“…Peptides were analyzed by reverse phase liquid chromatography with tandem mass spectrometry (LC–MS/MS) using an Ultimate 3000 LC system and a TripleTOF 5600 mass spectrometer, set in data-independent acquisition (DIA) under the same parameters as reported previously [ 23 ]. Data were analyzed using the integrated software suite DIA-NN [ 24 ], an automated pipeline especially developed to process DIA data.…”

Section: Methodsmentioning

confidence: 99%

Proteomics of the dentate gyrus reveals semantic dementia specific molecular pathology

Mol

Miedema

Melhem

et al. 2022

acta neuropathol commun

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Semantic dementia (SD) is a clinical subtype of frontotemporal dementia consistent with the neuropathological diagnosis frontotemporal lobar degeneration (FTLD) TDP type C, with characteristic round TDP-43 protein inclusions in the dentate gyrus. Despite this striking clinicopathological concordance, the pathogenic mechanisms are largely unexplained forestalling the development of targeted therapeutics. To address this, we carried out laser capture microdissection of the dentate gyrus of 15 SD patients and 17 non-demented controls, and assessed relative protein abundance changes by label-free quantitative mass spectrometry. To identify SD specific proteins, we compared our results to eight other FTLD and Alzheimer’s disease (AD) proteomic datasets of cortical brain tissue, parallel with functional enrichment analyses and protein–protein interactions (PPI). Of the total 5,354 quantified proteins, 151 showed differential abundance in SD patients (adjusted P-value < 0.01). Seventy-nine proteins were considered potentially SD specific as these were not detected, or demonstrated insignificant or opposite change in FTLD/AD. Functional enrichment indicated an overrepresentation of pathways related to the immune response, metabolic processes, and cell-junction assembly. PPI analysis highlighted a cluster of interacting proteins associated with adherens junction and cadherin binding, the cadherin-catenin complex. Multiple proteins in this complex showed significant upregulation in SD, including β-catenin (CTNNB1), γ-catenin (JUP), and N-cadherin (CDH2), which were not observed in other neurodegenerative proteomic studies, and hence may resemble SD specific involvement. A trend of upregulation of all three proteins was observed by immunoblotting of whole hippocampus tissue, albeit only significant for N-cadherin. In summary, we discovered a specific increase of cell adhesion proteins in SD constituting the cadherin-catenin complex at the synaptic membrane, essential for synaptic signaling. Although further investigation and validation are warranted, we anticipate that these findings will help unravel the disease processes underlying SD.

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“…SNX4 heterodimers and SNX8 homodimers are evolutionarily conserved complexes that localize on endosomes where they generate tubular profiles that are distinct from those of ESCPE-1 [32][33][34] (Figure 1B). In mammalian cells, SNX4 is involved in the recycling of TfR to the plasma membrane, and in autophagic membrane trafficking 32,[35][36][37] while SNX8 has a largely uncharacterised function (Figure 1B).…”

Section: Overview Of Snx-bar Proteinsmentioning

confidence: 99%

Out of the ESCPE room: Emerging roles of endosomal SNX‐BARs in receptor transport and host–pathogen interaction

Simonetti

Daly

Cullen

2023

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Several functions of the human cell, such as sensing nutrients, cell movement and interaction with the surrounding environment, depend on a myriad of transmembrane proteins and their associated proteins and lipids (collectively termed “cargoes”). To successfully perform their tasks, cargo must be sorted and delivered to the right place, at the right time, and in the right amount. To achieve this, eukaryotic cells have evolved a highly organized sorting platform, the endosomal network. Here, a variety of specialized multiprotein complexes sort cargo into itineraries leading to either their degradation or their recycling to various organelles for further rounds of reuse. A key sorting complex is the Endosomal SNX‐BAR Sorting Complex for Promoting Exit (ESCPE‐1) that promotes the recycling of an array of cargos to the plasma membrane and/or the trans‐Golgi network. ESCPE‐1 recognizes a hydrophobic‐based sorting motif in numerous cargoes and orchestrates their packaging into tubular carriers that pinch off from the endosome and travel to the target organelle. A wide range of pathogens mimic this sorting motif to hijack ESCPE‐1 transport to promote their invasion and survival within infected cells. In other instances, ESCPE‐1 exerts restrictive functions against pathogens by limiting their replication and infection. In this review, we discuss ESCPE‐1 assembly and functions, with a particular focus on recent advances in the understanding of its role in membrane trafficking, cellular homeostasis and host–pathogen interaction.

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The endosomal protein sorting nexin 4 is a synaptic protein

Cited by 14 publications

References 33 publications

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

Proteomics of the dentate gyrus reveals semantic dementia specific molecular pathology

Out of the ESCPE room: Emerging roles of endosomal SNX‐BARs in receptor transport and host–pathogen interaction

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