SCIENCE@home

Dysfunction of the ubiquitin ligase E3A Ube3A/E6-AP contributes to synaptic pathology in Alzheimer’s disease

M. Olabarria,S. Pasini,C. Corona,Pablo A. Robador,Cheng Song,H. Patel,R. Lefort

Published 2019 in Communications Biology

ABSTRACT

Synaptic dysfunction and synapse loss are prominent features in Alzheimer’s disease. Members of the Rho-family of guanosine triphosphatases, specifically RhoA, and the synaptic protein Arc are implicated in these pathogenic processes. They share a common regulatory molecule, the E3 ligase Ube3A/E6-AP. Here, we show that Ube3A is reduced in an Alzheimer’s disease mouse model, Tg2576 mouse, which overexpresses human APP695 carrying the Swedish mutation, and accumulates Aβ in the brain. Depletion of Ube3A precedes the age-dependent behavioral deficits and loss of dendritic spines in these mice, and results from a decrease in solubility following phosphorylation by c-Abl, after Aβ exposure. Loss of Ube3A triggers the accumulation of Arc and Ephexin-5, driving internalization of GluR1, and activation of RhoA, respectively, culminating in pruning of synapses, which is blocked by restoring Ube3A. Taken together, our results place Ube3A as a critical player in Alzheimer’s disease pathogenesis, and as a potential therapeutic target. Markel Olabarria et al. show that the loss of Ube3A plays a critical role in synaptic dysfunction, using an Alzheimer’s disease mouse model. This study establishes a molecular pathway that maintains a synaptic function and suggests Ube3A as a potential therapeutic target for Alzheimer’s disease.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-84 of 84 references · Page 1 of 1

CITED BY

Showing 1-28 of 28 citing papers · Page 1 of 1