Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel

Umanah, George K.E.; Pignatelli, Marco; Yin, Xiling; Chen, Rong; Crawford, Joshua; Neifert, Stewart; Scarffe, Leslie A.; Behensky, Adam; Guiberson, Noah Guy Lewis; Chang, Melissa I.; Ma, Erica; Kim, Jin Wan; Castro, Cibele Canal; Mao, Xiaobo; Chen, Li; Andrabi, Shaida A.; Pletnikov, Mikhail V.; Pulver, Ann E.; Avramopoulos, Dimitrios; Bonci, Antonello; Valle, David; Dawson, Ted M.; Dawson, Valina L.

doi:10.1126/scitranslmed.aah4985

Cited by 19 publications

(27 citation statements)

References 39 publications

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“…Furthermore, according to this hypothesis, treatment to restore the balance in AMPA transmission by blocking exaggerated AMPA downregulation may provide clinical benefit specifically an increase in learning potential. The size of the change in surface GluA2 AMPA induced by the A350V mutation is similar to what has been reported in mutations in the Thorase gene (Umanah et al, 2017; Piard et al, 2018) where pharmacological attempts to restore normal surface AMPA activity have shown therapeutic benefit in man (Ahrens-Nicklaus et al, 2017).…”

Section: Discussionsupporting

confidence: 82%

“…To determine the relative distribution of surface AMPA receptors in the hippocampus of IQSEC2 A350V as compared to wild type IQSEC2 a surface protein-crosslinking assay was performed using membrane-impermeant crosslinking agent, Bis(sulphosuccinimidyl)suberate (BS 3 , Sigma) as previously described (Umanah et al, 2017) with some modifications. Bis(sulphosuccinimidyl)suberate (BS 3 ) is a membrane-impermeant crosslinking agent that selectively crosslinks cell-surface proteins, forming high-molecular-mass aggregates.…”

Section: Methodsmentioning

confidence: 99%

“…Mice were anesthetized and transcardially perfused with 4% paraformaldehyde (PFA) in PBS after a brief vascular system washing with PBS as previously described (Umanah et al, 2017). After perfusion, brains were removed and postfixed overnight with 4% PFA plus 4% sucrose in PBS.…”

Section: Methodsmentioning

confidence: 99%

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An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

Rogers

Jada

Schragenheim-Rozales

et al. 2019

Front. Mol. Neurosci.

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We have recently described an A350V mutation in IQSEC2 associated with intellectual disability, autism and epilepsy. We sought to understand the molecular pathophysiology of this mutation with the goal of developing targets for drug intervention. We demonstrate here that the A350V mutation results in interference with the binding of apocalmodulin to the IQ domain of IQSEC2. We further demonstrate that this mutation results in constitutive activation of the guanine nucleotide exchange factor (GEF) activity of IQSEC2 resulting in increased production of the active form of Arf6. In a CRISPR generated mouse model of the A350V IQSEC2 mutation, we demonstrate that the surface expression of GluA2 AMPA receptors in mouse hippocampal tissue was significantly reduced in A350V IQSEC2 mutant mice compared to wild type IQSEC2 mice and that there is a significant reduction in basal synaptic transmission in the hippocampus of A350V IQSEC2 mice compared to wild type IQSEC2 mice. Finally, the A350V IQSEC2 mice demonstrated increased activity, abnormal social behavior and learning as compared to wild type IQSEC2 mice. These findings suggest a model of how the A350V mutation in IQSEC2 may mediate disease with implications for targets for drug therapy. These studies provide a paradigm for a personalized approach to precision therapy for a disease that heretofore has no therapy.

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Section: Discussionsupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

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An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

Rogers

Jada

Schragenheim-Rozales

et al. 2019

Front. Mol. Neurosci.

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“…Given that we now find that autocrine IL23 is critical for macrophage-mediated proinflammatory responses, macrophages might constitute a beneficial IL23 pathway therapeutic target in IBD patients, in addition to the likely beneficial outcome of targeting IL23 on T cells. As receptor recycling can affect therapeutic outcomes,39 40 understanding IL23R surface regulation might ultimately contribute to strategic design of therapies targeting this pathway. We identify IL23R as critical in signalling and amplification of PRR-induced cytokines in human macrophages, thereby further elucidating how IL23R and the IBD-protective IL23R variant regulate innate immune outcomes directly relevant in intestinal immune homeostasis.…”

Section: Discussionmentioning

confidence: 99%

IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes

Sun

Hedl

Abraham

2019

Gut

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ObjectiveThe interleukin (IL)23 pathway contributes to IBD pathogenesis and is being actively studied as a therapeutic target in patients with IBD. Unexpected outcomes in these therapeutic trials have highlighted the importance of understanding the cell types and mechanisms through which IL23 regulates immune outcomes. How IL23 regulates macrophage outcomes and the consequences of the IL23R R381Q IBD-protective variant on macrophages are not well defined; macrophages are key players in IBD pathogenesis and inflammation.DesignWe analysed protein and RNA expression, signalling and localisation in human monocyte-derived macrophages (MDMs) through western blot, ELISA, real-time PCR, flow cytometry, immunoprecipitation and microscopy.ResultsIL23R was critical for optimal levels of pattern-recognition receptor (PRR)-induced signalling and cytokines in human MDMs. In contrast to the coreceptor IL12Rβ1, IL23 induced dynamic IL23R cell surface regulation and this required clathrin and dynamin-mediated endocytosis and endocytic recycling-dependent pathways; these pathways were essential for IL23R-mediated outcomes. The IBD-protective IL23R R381Q variant showed distinct outcomes. Relative to IL23R R381, HeLa cells expressing IL23R Q381 showed decreased IL23R recycling and reduced assembly of IL23R Q381 with Janus kinase/signal transducer and activator of transcription pathway members. In MDMs from IL23R Q381 carriers, IL23R accumulated in late endosomes and lysosomes on IL23 treatment and cells demonstrated decreased IL23R- and PRR-induced signalling and cytokines relative to IL23R R381 MDMs.ConclusionMacrophage-mediated inflammatory pathways are key contributors to IBD pathogenesis, and we identify an autocrine/paracrine IL23 requirement in PRR-initiated human macrophage outcomes and in human intestinal myeloid cells, establish that IL23R undergoes ligand-induced recycling, define mechanisms regulating IL23R-induced signalling and determine how the IBD-protective IL23R R381Q variant modulates these processes.

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“…Upon Thorase depletion, AMPAR internalization and LTD are consequently decreased, while LTP is enhanced [ 78 ]. Thorase-deficient mice display disrupted AMPAR internalization and recycling and behavioral deficits, which can be rescued by the FDA-approved drug Perampanel [ 79 ]. Interestingly, Thorase variants have been found in schizophrenia patients and Perampanel use in patients improved hypertonicity and resolution of seizures, showing a promising start [ 80 ].…”

Section: Pdz Domain-containing Interactantsmentioning

confidence: 99%

AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking

Bissen

Foss

Acker‐Palmer

2019

Cell. Mol. Life Sci.

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To correctly transfer information, neuronal networks need to continuously adjust their synaptic strength to extrinsic stimuli. This ability, termed synaptic plasticity, is at the heart of their function and is, thus, tightly regulated. In glutamatergic neurons, synaptic strength is controlled by the number and function of AMPA receptors at the postsynapse, which mediate most of the fast excitatory transmission in the central nervous system. Their trafficking to, at, and from the synapse, is, therefore, a key mechanism underlying synaptic plasticity. Intensive research over the last 20 years has revealed the increasing importance of interacting proteins, which accompany AMPA receptors throughout their lifetime and help to refine the temporal and spatial modulation of their trafficking and function. In this review, we discuss the current knowledge about the roles of key partners in regulating AMPA receptor trafficking and focus especially on the movement between the intracellular, extrasynaptic, and synaptic pools. We examine their involvement not only in basal synaptic function, but also in Hebbian and homeostatic plasticity. Included in our review are well-established AMPA receptor interactants such as GRIP1 and PICK1, the classical auxiliary subunits TARP and CNIH, and the newest additions to AMPA receptor native complexes.

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Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel

Cited by 19 publications

References 39 publications

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes

AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking

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