GluA1 subunit ubiquitination mediates amyloid-beta-induced loss of surface alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors

Guntupalli, Sumasri, Jang, Se Eun, Zhu, Tianyi, Huganir, Richard L., Widagdo, Jocelyn and Anggono, Victor (2017) GluA1 subunit ubiquitination mediates amyloid-beta-induced loss of surface alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Journal of Biological Chemistry, 292 20: 8186-8194. doi:10.1074/jbc.M116.774554


Author Guntupalli, Sumasri
Jang, Se Eun
Zhu, Tianyi
Huganir, Richard L.
Widagdo, Jocelyn
Anggono, Victor
Title GluA1 subunit ubiquitination mediates amyloid-beta-induced loss of surface alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
0021-9258
Publication date 2017-05-19
Year available 2017
Sub-type Article (original research)
DOI 10.1074/jbc.M116.774554
Open Access Status DOI
Volume 292
Issue 20
Start page 8186
End page 8194
Total pages 9
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Abstract The accumulation of soluble amyloid-β (Aβ) peptides produces profound neuronal changes in the brain during the pathogenesis of Alzheimer's disease. Excessive levels of Aβ disrupt excitatory synaptic transmission by promoting the removal of synaptic AMPA receptors (AMPARs), dendritic spine loss, and synaptic depression. Recently, activity-dependent ubiquitination of the GluA1 subunit has been shown to regulate the intracellular sorting of AMPARs toward late endosomes for degradation. However, whether this ubiquitin signaling pathway mediates Aβ-induced loss of surface AMPARs is unknown. In this study, we demonstrate that acute exposure of cultured neurons to soluble Aβ oligomers induces AMPAR ubiquitination concomitant with the removal of AMPARs from the plasma membrane. Importantly, expression of the GluA1 ubiquitin-deficient mutants inhibited the adverse effects of Aβ on the surface expression of AMPARs in neurons. Furthermore, we revealed the cross-talk between GluA1 ubiquitination and phosphorylation, in particular phosphorylation at Ser-845, which is crucial for AMPAR recycling and is known to be dephosphorylated in the presence of Aβ. Our data showed that the GluA1 ubiquitin-deficient mutant enhances GluA1 phosphorylation on Ser-845. Conversely, the GluA1 S845D phosphomimetic mutant reduced binding with Nedd4-1 and hence the ubiquitination of AMPARs. Importantly, the GluA1 S845D mutant also prevented Aβ-induced removal of surface AMPARs. Taken together, these findings provide the first demonstration of the dynamic cross-modulation of GluA1 ubiquitination and phosphorylation, a process that is perturbed by Aβ, in regulating the membrane sorting decision that ultimately determines the number of AMPARs on the cell surface.
Formatted abstract
The accumulation of soluble amyloid-β (Aβ) peptides produces profound neuronal changes in the brain during the pathogenesis of Alzheimer's disease. Excessive levels of Aβ disrupt excitatory synaptic transmission by promoting the removal of synaptic AMPA receptors (AMPARs), dendritic spine loss, and synaptic depression. Recently, activity-dependent ubiquitination of the GluA1 subunit has been shown to regulate the intracellular sorting of AMPARs toward late endosomes for degradation. However, whether this ubiquitin signaling pathway mediates Aβ-induced loss of surface AMPARs is unknown. In this study, we demonstrate that acute exposure of cultured neurons to soluble Aβ oligomers induces AMPAR ubiquitination concomitant with the removal of AMPARs from the plasma membrane. Importantly, expression of the GluA1 ubiquitin-deficient mutants inhibited the adverse effects of Aβ on the surface expression of AMPARs in neurons. Furthermore, we revealed the cross-talk between GluA1 ubiquitination and phosphorylation, in particular phosphorylation at Ser-845, which is crucial for AMPAR recycling and is known to be dephosphorylated in the presence of Aβ. Our data showed that the GluA1 ubiquitin-deficient mutant enhances GluA1 phosphorylation on Ser-845. Conversely, the GluA1 S845D phosphomimetic mutant reduced binding with Nedd4-1 and hence the ubiquitination of AMPARs. Importantly, the GluA1 S845D mutant also prevented Aβ-induced removal of surface AMPARs. Taken together, these findings provide the first demonstration of the dynamic cross-modulation of GluA1 ubiquitination and phosphorylation, a process that is perturbed by Aβ, in regulating the membrane sorting decision that ultimately determines the number of AMPARs on the cell surface.
Keyword α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR)
Amyloid-β (Aβ)
Phosphorylation
Trafficking
Ubiquitylation (ubiquitination)
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID DGP14-57
GNT1083209
P50AG005146
DE170100112
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
 
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Created: Mon, 22 May 2017, 19:16:23 EST by Victor Anggono on behalf of Clem Jones Centre for Ageing Dementia Research