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

Olabarria, Markel; Pasini, Silvia; Corona, Carlo; Robador, Pablo; Song, Chun-Yan; Patel, Hardik J.; Lefort, Roger

doi:10.1038/s42003-019-0350-5

Cited by 23 publications

(18 citation statements)

References 70 publications

(104 reference statements)

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“…We previously reported that modulation of Ephexin5 can ameliorate learning and memory deficits in Alzheimer’s disease (AD) 19 , 47 . Interestingly, a recent study links loss of UBE3A in AD to elevation of Ephexin5 and disease progression 48 . This study also supports Ephexin5 as a substrate of UBE3A in pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

Sell

Xin

Cook

et al. 2021

Sci Rep

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In humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in > 1–2% of patients with autism spectrum disorders—a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 can be directly ubiquitylated by UBE3A. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

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Section: Discussionmentioning

confidence: 99%

Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

Sell

Xin

Cook

et al. 2021

Sci Rep

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“…The HECT E3 ligase Ube3A has described roles in synaptic function and plasticity, both of which are affected in AD patients ( Sun et al, 2015 ). Synaptic dysfunction and synapse loss are prominent features of AD ( Olabarria et al, 2019 ). In a mouse model that overexpresses APPswe, resulting in accumulation of Aβ in the brain, Ube3A expression is reduced ( Olabarria et al, 2019 ).…”

Section: E3 Ligases With Expression Changes In Alzheimer’s Diseasementioning

confidence: 99%

“…Activated microglia can cause synaptic loss and release pro-inflammatory kinases, resulting in synaptic toxicity ( Jackson et al, 2019 ). E3 ligases that are implicated in synaptic loss and/or dysfunction include ubiquitin protein ligase E3A (Ube3A) and NEDD4-1 ( Rodrigues et al, 2016 ; Olabarria et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function

Potjewyd

Axtman

2021

Front. Cell. Neurosci.

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The Ubiquitin Proteasome System (UPS) is responsible for the degradation of misfolded or aggregated proteins via a multistep ATP-dependent proteolytic mechanism. This process involves a cascade of ubiquitin (Ub) transfer steps from E1 to E2 to E3 ligase. The E3 ligase transfers Ub to a targeted protein that is brought to the proteasome for degradation. The inability of the UPS to remove misfolded or aggregated proteins due to UPS dysfunction is commonly observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). UPS dysfunction in AD drives disease pathology and is associated with the common hallmarks such as amyloid-β (Aβ) accumulation and tau hyperphosphorylation, among others. E3 ligases are key members of the UPS machinery and dysfunction or changes in their expression can propagate other aberrant processes that accelerate AD pathology. The upregulation or downregulation of expression or activity of E3 ligases responsible for these processes results in changes in protein levels of E3 ligase substrates, many of which represent key proteins that propagate AD. A powerful way to better characterize UPS dysfunction in AD and the role of individual E3 ligases is via the use of high-quality chemical tools that bind and modulate specific E3 ligases. Furthermore, through combining gene editing with recent advances in 3D cell culture, in vitro modeling of AD in a dish has become more relevant and possible. These cell-based models of AD allow for study of specific pathways and mechanisms as well as characterization of the role E3 ligases play in driving AD. In this review, we outline the key mechanisms of UPS dysregulation linked to E3 ligases in AD and highlight the currently available chemical modulators. We present several key approaches for E3 ligase ligand discovery being employed with respect to distinct classes of E3 ligases. Where possible, specific examples of the use of cultured neurons to delineate E3 ligase biology have been captured. Finally, utilizing the available ligands for E3 ligases in the design of proteolysis targeting chimeras (PROTACs) to degrade aberrant proteins is a novel strategy for AD, and we explore the prospects of PROTACs as AD therapeutics.

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“…GABRA5 (gamma-aminobutyric acid type A receptor subunit alpha5) [142,143]. UBE3A (ubiquitin-protein ligase E3A) [144][145][146]. CYFIP1 (cytoplasmic FMR1-interacting protein 1) [147,148].…”

Section: Genes and Geneticsmentioning

confidence: 99%

Symptomatic, Genetic, and Mechanistic Overlaps between Autism and Alzheimer’s Disease

et al. 2021

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Autism spectrum disorder (ASD) and Alzheimer’s disease (AD) are neurodevelopmental and neurodegenerative disorders affecting two opposite ends of life span, i.e., childhood and old age. Both disorders pose a cumulative threat to human health, with the rate of incidences increasing considerably worldwide. In the context of recent developments, we aimed to review correlated symptoms and genetics, and overlapping aspects in the mechanisms of the pathogenesis of ASD and AD. Dementia, insomnia, and weak neuromuscular interaction, as well as communicative and cognitive impairments, are shared symptoms. A number of genes and proteins linked with both disorders have been tabulated, including MECP2, ADNP, SCN2A, NLGN, SHANK, PTEN, RELN, and FMR1. Theories about the role of neuron development, processing, connectivity, and levels of neurotransmitters in both disorders have been discussed. Based on the recent literature, the roles of FMRP (Fragile X mental retardation protein), hnRNPC (heterogeneous ribonucleoprotein-C), IRP (Iron regulatory proteins), miRNAs (MicroRNAs), and α-, β0, and γ-secretases in the posttranscriptional regulation of cellular synthesis and processing of APP (amyloid-β precursor protein) have been elaborated to describe the parallel and overlapping routes and mechanisms of ASD and AD pathogenesis. However, the interactive role of genetic and environmental factors, oxidative and metal ion stress, mutations in the associated genes, and alterations in the related cellular pathways in the development of ASD and AD needs further investigation.

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

Cited by 23 publications

References 70 publications

Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function

Symptomatic, Genetic, and Mechanistic Overlaps between Autism and Alzheimer’s Disease

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