期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 292, 期 20, 页码 8186-8194出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.774554
关键词
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资金
- John T. Reid Charitable Trusts
- Alzheimer's Australia Dementia Research Foundation [DGP14-57]
- Australian National Health and Medical Research Council [GNT1083209, GNT1099114, 477108]
- Clem Jones Centre for Ageing Dementia Research
- National Institutes of Health [P50AG005146]
- Millipore Corporation
- University of Queensland International Scholarships
- Australian Research Council Discovery Early Career Researcher Award [DE170100112]
- Australian Research Council [DE170100112] Funding Source: Australian Research Council
The accumulation of soluble amyloid-beta (A beta) peptides produces profound neuronal changes in the brain during the pathogenesis of Alzheimer's disease. Excessive levels of A beta 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 A beta-induced loss of surface AMPARs is unknown. In this study, we demonstrate that acute exposure of cultured neurons to soluble A beta 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 A beta 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 A beta. 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 A beta-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 A beta, in regulating the membrane sorting decision that ultimately determines the number of AMPARs on the cell surface.
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