title: GluA1 subunit ubiquitination mediates amyloid-β-induced loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.
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.
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Sumasri
authors.initials: S
authors.lastname: Guntupalli
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Jang
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Department of Neuroscience and Kavli Neuroscience Discovery Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Widagdo
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: v.anggono@uq.edu.au.
authors.forename: Victor
authors.initials: V
authors.lastname: Anggono
mesh_terms: D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D000075702:Nedd4 Ubiquitin Protein Ligases; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D016229:Amyloid beta-Peptides; D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; D010446:Peptide Fragments; D018091:Receptors, AMPA; D044767:Ubiquitin-Protein Ligases; C075222:amyloid beta-protein (1-42); C000618479:NEDD4L protein, rat; C000618484:Nedd4 protein, rat
keywords: amyloid-β (Aβ); phosphorylation; trafficking; ubiquitylation (ubiquitination); α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR)