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A role for sorting nexin 27 in AMPA receptor trafficking.

Loo LS, Tang N, Al-Haddawi M, Dawe GS, Hong W - Nat Commun (2014)

Bottom Line: Mechanistically, SNX27 interacts with K-ras GTPase via the RA domain; and following chemical LTP stimuli, K-ras is recruited to SNX27-enriched endosomes through a Ca(2+)/CaM-dependent mechanism, which in turn drives the synaptic delivery of homomeric GluA1 receptors.Impairment of SNX27 prevents LTP and associated trafficking of AMPARs.These results demonstrate a role for SNX27 in neuronal plasticity, provide a molecular explanation for the K-ras signal during LTP and identify SNX27 as the PDZ-containing molecular linker that couples the plasticity stimuli to the delivery of postsynaptic cargo.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Molecular and Cell Biology, Singapore 138673, Singapore [2] Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553, Singapore.

ABSTRACT
Sorting nexin 27 (SNX27), a PDZ domain-containing endosomal protein, was recently shown to modulate glutamate receptor recycling in Down's syndrome. However, the precise molecular role of SNX27 in GluA1 trafficking is unclear. Here we report that SNX27 is enriched in dendrites and spines, along with recycling endosomes. Significantly, the mobilization of SNX27 along with recycling endosomes into spines was observed. Mechanistically, SNX27 interacts with K-ras GTPase via the RA domain; and following chemical LTP stimuli, K-ras is recruited to SNX27-enriched endosomes through a Ca(2+)/CaM-dependent mechanism, which in turn drives the synaptic delivery of homomeric GluA1 receptors. Impairment of SNX27 prevents LTP and associated trafficking of AMPARs. These results demonstrate a role for SNX27 in neuronal plasticity, provide a molecular explanation for the K-ras signal during LTP and identify SNX27 as the PDZ-containing molecular linker that couples the plasticity stimuli to the delivery of postsynaptic cargo.

No MeSH data available.


Related in: MedlinePlus

Histopathological changes in the SNX27−/− brain.(a) Representative coronal brain section from SNX27−/− mouse stained with haematoxylin and eosin (H&E). There was dilatation of the lateral ventricle (LV), periventricular neuropil dissociation (arrow) with a rim of cortical tissue at the periphery (asterisk). Scale bar, 2 mm (b) Representative saggital sections from SNX27−/− brain stained with H&E. Scale bar, 3 mm. (c) Hippocampal CA1 region from SNX27−/− and WT mice (left and right panels, respectively). Inset shows region where the images were obtained. Scale bar, 40 μm. (d) Hippocampal dentate gyrus(DG) from SNX27−/− and WT mice (left and right panels respectively). Notable features include vacuolation of pyramidal neurons, thinning of dentate gyrus layer and cytoplasmic vacuolation. Inset shows region where the images were obtained. Scale bar, 100 μm.
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f1: Histopathological changes in the SNX27−/− brain.(a) Representative coronal brain section from SNX27−/− mouse stained with haematoxylin and eosin (H&E). There was dilatation of the lateral ventricle (LV), periventricular neuropil dissociation (arrow) with a rim of cortical tissue at the periphery (asterisk). Scale bar, 2 mm (b) Representative saggital sections from SNX27−/− brain stained with H&E. Scale bar, 3 mm. (c) Hippocampal CA1 region from SNX27−/− and WT mice (left and right panels, respectively). Inset shows region where the images were obtained. Scale bar, 40 μm. (d) Hippocampal dentate gyrus(DG) from SNX27−/− and WT mice (left and right panels respectively). Notable features include vacuolation of pyramidal neurons, thinning of dentate gyrus layer and cytoplasmic vacuolation. Inset shows region where the images were obtained. Scale bar, 100 μm.

Mentions: All homozygous SNX27−/− mice are smaller, weaker, have dome-shaped heads of varying severity and display abnormal behaviours compared with their wild-type littermates. Grossly, the brains from SNX27-deficient mice were evidently pale and displayed accumulation of cerebrospinal fluid in the lateral ventricles, which collapsed upon cut (Fig. 1a,b, Supplementary Fig. 1). Histological examination revealed variable degrees of bilateral dilatation of lateral ventricles, reduced thickness of cerebral cortex and dissociation of periventricular neuropil (Fig. 1a,b). The other major notable changes were seen in the hippocampus, which displayed vacuolation of the neuropil and CA1 and CA2 pyramidal neurons, (Fig. 1c) and thinning of dentate gyrus layer (Fig. 1d). Strikingly, quantification of the dentate gyrus layer showed that the thickness was reduced by ~30% compared with WT.


A role for sorting nexin 27 in AMPA receptor trafficking.

Loo LS, Tang N, Al-Haddawi M, Dawe GS, Hong W - Nat Commun (2014)

Histopathological changes in the SNX27−/− brain.(a) Representative coronal brain section from SNX27−/− mouse stained with haematoxylin and eosin (H&E). There was dilatation of the lateral ventricle (LV), periventricular neuropil dissociation (arrow) with a rim of cortical tissue at the periphery (asterisk). Scale bar, 2 mm (b) Representative saggital sections from SNX27−/− brain stained with H&E. Scale bar, 3 mm. (c) Hippocampal CA1 region from SNX27−/− and WT mice (left and right panels, respectively). Inset shows region where the images were obtained. Scale bar, 40 μm. (d) Hippocampal dentate gyrus(DG) from SNX27−/− and WT mice (left and right panels respectively). Notable features include vacuolation of pyramidal neurons, thinning of dentate gyrus layer and cytoplasmic vacuolation. Inset shows region where the images were obtained. Scale bar, 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921469&req=5

f1: Histopathological changes in the SNX27−/− brain.(a) Representative coronal brain section from SNX27−/− mouse stained with haematoxylin and eosin (H&E). There was dilatation of the lateral ventricle (LV), periventricular neuropil dissociation (arrow) with a rim of cortical tissue at the periphery (asterisk). Scale bar, 2 mm (b) Representative saggital sections from SNX27−/− brain stained with H&E. Scale bar, 3 mm. (c) Hippocampal CA1 region from SNX27−/− and WT mice (left and right panels, respectively). Inset shows region where the images were obtained. Scale bar, 40 μm. (d) Hippocampal dentate gyrus(DG) from SNX27−/− and WT mice (left and right panels respectively). Notable features include vacuolation of pyramidal neurons, thinning of dentate gyrus layer and cytoplasmic vacuolation. Inset shows region where the images were obtained. Scale bar, 100 μm.
Mentions: All homozygous SNX27−/− mice are smaller, weaker, have dome-shaped heads of varying severity and display abnormal behaviours compared with their wild-type littermates. Grossly, the brains from SNX27-deficient mice were evidently pale and displayed accumulation of cerebrospinal fluid in the lateral ventricles, which collapsed upon cut (Fig. 1a,b, Supplementary Fig. 1). Histological examination revealed variable degrees of bilateral dilatation of lateral ventricles, reduced thickness of cerebral cortex and dissociation of periventricular neuropil (Fig. 1a,b). The other major notable changes were seen in the hippocampus, which displayed vacuolation of the neuropil and CA1 and CA2 pyramidal neurons, (Fig. 1c) and thinning of dentate gyrus layer (Fig. 1d). Strikingly, quantification of the dentate gyrus layer showed that the thickness was reduced by ~30% compared with WT.

Bottom Line: Mechanistically, SNX27 interacts with K-ras GTPase via the RA domain; and following chemical LTP stimuli, K-ras is recruited to SNX27-enriched endosomes through a Ca(2+)/CaM-dependent mechanism, which in turn drives the synaptic delivery of homomeric GluA1 receptors.Impairment of SNX27 prevents LTP and associated trafficking of AMPARs.These results demonstrate a role for SNX27 in neuronal plasticity, provide a molecular explanation for the K-ras signal during LTP and identify SNX27 as the PDZ-containing molecular linker that couples the plasticity stimuli to the delivery of postsynaptic cargo.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Molecular and Cell Biology, Singapore 138673, Singapore [2] Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553, Singapore.

ABSTRACT
Sorting nexin 27 (SNX27), a PDZ domain-containing endosomal protein, was recently shown to modulate glutamate receptor recycling in Down's syndrome. However, the precise molecular role of SNX27 in GluA1 trafficking is unclear. Here we report that SNX27 is enriched in dendrites and spines, along with recycling endosomes. Significantly, the mobilization of SNX27 along with recycling endosomes into spines was observed. Mechanistically, SNX27 interacts with K-ras GTPase via the RA domain; and following chemical LTP stimuli, K-ras is recruited to SNX27-enriched endosomes through a Ca(2+)/CaM-dependent mechanism, which in turn drives the synaptic delivery of homomeric GluA1 receptors. Impairment of SNX27 prevents LTP and associated trafficking of AMPARs. These results demonstrate a role for SNX27 in neuronal plasticity, provide a molecular explanation for the K-ras signal during LTP and identify SNX27 as the PDZ-containing molecular linker that couples the plasticity stimuli to the delivery of postsynaptic cargo.

No MeSH data available.


Related in: MedlinePlus