Dataset Information

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

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.

SUBMITTER: Olabarria M

PROVIDER: S-EPMC6430817 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Olabarria Markel M Pasini Silvia S Corona Carlo C Robador Pablo P Song Cheng C Patel Hardik H Lefort Roger R

Communications biology 20190322

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 o ...[more]

PMID: 30937395

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Project description:Background:Although neuronal extracellular sensing is emerging as crucial for brain wiring and therefore plasticity, little is known about these processes in neurodevelopmental disorders. Ubiquitin protein ligase E3A (UBE3A) plays a key role in neurodevelopment. Lack of UBE3A leads to Angelman syndrome (AS), while its increase is among the most prevalent genetic causes of autism (e.g., Dup15q syndrome). By using microstructured substrates that can induce specific directional stimuli in cells, we previously found deficient topographical contact guidance in AS neurons, which was linked to a dysregulated activation of the focal adhesion pathway. Methods:Here, we study axon and dendrite contact guidance and neuronal morphological features of wild-type, AS, and UBE3A-overexpressing neurons (Dup15q autism model) on micrograting substrates, with the aim to clarify the role of UBE3A in neuronal guidance. Results:We found that loss of axonal contact guidance is specific for AS neurons while UBE3A overexpression does not affect neuronal directional polarization along microgratings. Deficits at the level of axonal branching, growth cone orientation and actin fiber content, focal adhesion (FA) effectors, and actin fiber-binding proteins were observed in AS neurons. We tested different rescue strategies for restoring correct topographical guidance in AS neurons on microgratings, by either UBE3A protein re-expression or by pharmacological treatments acting on cytoskeleton contractility. Nocodazole, a drug that depolymerizes microtubules and increases cell contractility, rescued AS axonal alignment to the gratings by partially restoring focal adhesion pathway activation. Surprisingly, UBE3A re-expression only resulted in partial rescue of the phenotype. Conclusions:We identified a specific in vitro deficit in axonal topographical guidance due selectively to the loss of UBE3A, and we further demonstrate that this defective guidance can be rescued to a certain extent by pharmacological or genetic treatment strategies. Overall, cytoskeleton dynamics emerge as important partners in UBE3A-mediated contact guidance responses. These results support the view that UBE3A-related deficits in early neuronal morphogenesis may lead to defective neuronal connectivity and plasticity.

Dataset Information

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

Publications

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

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