<scp><i>CYFIP2</i></scp> p.<scp>Arg87Cys</scp> Causes Neurological Defects and Degradation of <scp>CYFIP2</scp>

Kang, Muwon; Zhang, Yinhua; Kang, Hyae Rim; Kim, Seoyeong; Ma, Xiaoqiang; Yi, Yunho; Lee, Seung-Joon; Kim, Yoonhee; Li, Huiling; Jin, Can; Lee, Dongmin; Kim, Eunjoon; Han, Kihoon

doi:10.1002/ana.26535

Cited by 6 publications

(4 citation statements)

References 21 publications

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“…Consistent with the immunohistological analysis, CYFIP2 levels were reduced in hippocampal CA1 synaptosomal lysates from Cyfip2 cKO mice compared to control mice ( Figure 3 (B)). As expected, the WAVE1 protein, another component of the WRC, was also reduced in Cyfip2 cKO lysates because the stability of WAVE1 is inter-dependent with that of CYFIP2 (Han et al 2015 ; Zhang et al 2020 ; Kang et al 2023 ). In contrast, CYFIP1 levels were comparable between control and Cyfip2 cKO mice.…”

Section: Resultssupporting

confidence: 62%

“…The two members of the cytoplasmic FMR1-interacting protein family, CYFIP1 and CYFIP2, are evolutionarily conserved proteins whose genetic variants are causally associated with numerous brain disorders, including autism spectrum disorders, intellectual disability, schizophrenia, and epilepsy (Schenck et al 2001 ; Abekhoukh and Bardoni 2014 ; Zhang, Lee, et al 2019 ). Specifically, in the case of CYFIP2 , de novo variants have recently been identified in individuals diagnosed with neurodevelopmental disorders and early-onset epileptic encephalopathy characterized by developmental regression, intellectual disability, seizures, muscular hypotonia, and microcephaly (Nakashima et al 2018 ; Peng et al 2018 ; Lee et al 2019 ; Zhong et al 2019 ; Zweier et al 2019 ; Begemann et al 2021 ; Kang et al 2023 ).…”

Section: Introductionmentioning

confidence: 99%

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Cell-autonomous reduction of CYFIP2 is insufficient to induce Alzheimer's disease-like pathologies in the hippocampal CA1 pyramidal neurons of aged mice

Zhang

et al. 2023

Animal Cells and Systems

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Cytoplasmic FMR1-interacting protein 2 (CYFIP2) is an evolutionarily conserved multifunctional protein that regulates the neuronal actin cytoskeleton, mRNA translation and transport, and mitochondrial morphology and function. Supporting its critical roles in proper neuronal development and function, human genetic studies have repeatedly identified variants of the CYFIP2 gene in individuals diagnosed with neurodevelopmental disorders. Notably, a few recent studies have also suggested a mechanistic link between reduced CYFIP2 level and Alzheimer's disease (AD). Specifically, in the hippocampus of 12-month-old Cyfip2 heterozygous mice, several AD-like pathologies were identified, including increased levels of Tau phosphorylation and gliosis, and loss of dendritic spines in CA1 pyramidal neurons. However, detailed pathogenic mechanisms, such as cell types and their circuits where the pathologies originate, remain unknown for AD-like pathologies caused by CYFIP2 reduction. In this study, we aimed to address this issue by examining whether the cell-autonomous reduction of CYFIP2 in CA1 excitatory pyramidal neurons is sufficient to induce AD-like phenotypes in the hippocampus. We performed immunohistochemical, morphological, and biochemical analyses in 12-month-old Cyfip2 conditional knock-out mice, which have postnatally reduced CYFIP2 expression level in CA1, but not in CA3, excitatory pyramidal neurons of the hippocampus. Unexpectedly, we could not find any significant AD-like phenotype, suggesting that the CA1 excitatory neuron-specific reduction of CYFIP2 level is insufficient to lead to AD-like pathologies in the hippocampus. Therefore, we propose that CYFIP2 reduction in other neurons and/or their synaptic connections with CA1 pyramidal neurons may be critically involved in the hippocampal AD-like phenotypes of Cyfip2 heterozygous mice.

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Section: Resultssupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Cell-autonomous reduction of CYFIP2 is insufficient to induce Alzheimer's disease-like pathologies in the hippocampal CA1 pyramidal neurons of aged mice

Zhang

et al. 2023

Animal Cells and Systems

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“…Structural studies have demonstrated that Arg87 CYFIP2 variants likely disrupt hydrogen bonding between CYFIP2 and WAVE1 or Nap1, leading to structural instability of the WRC and dysregulation of Rac1-mediated WRC activity 132 . Intriguingly, Cyfip2 +/R87C knock-in mice recapitulate a variety of neurological phenotypes that resemble symptoms of patients with West syndrome 133 . Because West syndrome and Ohtahara syndrome are categorized as subtypes of EIEE 134 —both of which are known to involve presynaptic defects 135 —it will be interesting to examine how the reported functions of CYFIP2 are linked to their pathogenesis mechanisms.…”

Section: The Association Of Wrc Dysfunction With Brain Disordersmentioning

confidence: 99%

Orchestration of synaptic functions by WAVE regulatory complex-mediated actin reorganization

Han

2023

Exp Mol Med

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The WAVE regulatory complex (WRC), composed of five components—Cyfip1/Sra1, WAVE/Scar, Abi, Nap1/Nckap1, and Brk1/HSPC300—is essential for proper actin cytoskeletal dynamics and remodeling in eukaryotic cells, likely by matching various patterned signals to Arp2/3-mediated actin nucleation. Accumulating evidence from recent studies has revealed diverse functions of the WRC in neurons, demonstrating its crucial role in dictating the assembly of molecular complexes for the patterning of various trans-synaptic signals. In this review, we discuss recent exciting findings on the physiological role of the WRC in regulating synaptic properties and highlight the involvement of WRC dysfunction in various brain disorders.

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“…The cytoplasmic FMR1-interacting protein family, comprising CYFIP1 and CYFIP2, are evolutionarily conserved multifunctional proteins, and their dysfunction is causally associated with various brain disorders, including autism spectrum disorders, intellectual disability, schizophrenia, and early-onset epilepsy (Schenck et al 2001 ; Abekhoukh and Bardoni 2014 ; Zhang, Lee, et al 2019 ; Kang et al 2023 ). At the molecular level, CYFIP1/2 is a core component of the heteropentameric Wiskott – Aldrich syndrome protein family verprolin-homologous protein (WAVE) regulatory complex (WRC) that regulates actin polymerization and branching in various cell types (Chen ZC et al 2010 ; Lee Y et al 2017 ; Rottner et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Cell-autonomous reduction of CYFIP2 changes dendrite length, dendritic protrusion morphology, and inhibitory synapse density in the hippocampal CA1 pyramidal neurons of 17-month-old mice

Kim,

Ma,

Zhang

et al. 2024

Animal Cells and Systems

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The cytoplasmic FMR1-interacting protein 2 (CYFIP2) have diverse molecular functions in neurons, including the regulation of actin polymerization, mRNA translation, and mitochondrial morphology and function. Mutations in the CYFIP2 gene are associated with early-onset epilepsy and neurodevelopmental disorders, while decreases in its protein levels are linked to Alzheimer's disease (AD). Notably, previous research has revealed AD-like phenotypes, such as dendritic spine loss, in the hippocampal CA1 pyramidal neurons of 12-month-old Cyfip2 heterozygous mice but not of age-matched CA1 pyramidal neuron-specific Cyfip2 conditional knock-out (cKO) mice. This study aims to investigate whether dendritic spine loss in Cyfip2 cKO mice is merely delayed compared to Cyfip2 heterozygous mice, and to explore further neuronal phenotypes regulated by CYFIP2 in aged mice. We characterized dendrite and dendritic protrusion morphologies, along with excitatory/inhibitory synapse densities in CA1 pyramidal neurons of 17-month-old Cyfip2 cKO mice. Overall dendritic branching was normal, with a reduction in the length of basal, not apical, dendrites in CA1 pyramidal neurons of Cyfip2 cKO mice. Furthermore, while dendritic protrusion density remained normal, alterations were observed in the length of mushroom spines and the head volume of stubby spines in basal, not apical, dendrites of Cyfip2 cKO mice. Although excitatory synapse density remained unchanged, inhibitory synapse density increased in apical, not basal, dendrites of Cyfip2 cKO mice. Consequently, a cell-autonomous reduction of CYFIP2 appears insufficient to induce dendritic spine loss in CA1 pyramidal neurons of aged mice. However, CYFIP2 is required to maintain normal dendritic length, dendritic protrusion morphology, and inhibitory synapse density.

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CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2

Cited by 6 publications

References 21 publications

Cell-autonomous reduction of CYFIP2 is insufficient to induce Alzheimer's disease-like pathologies in the hippocampal CA1 pyramidal neurons of aged mice

Cell-autonomous reduction of CYFIP2 is insufficient to induce Alzheimer's disease-like pathologies in the hippocampal CA1 pyramidal neurons of aged mice

Orchestration of synaptic functions by WAVE regulatory complex-mediated actin reorganization

Cell-autonomous reduction of CYFIP2 changes dendrite length, dendritic protrusion morphology, and inhibitory synapse density in the hippocampal CA1 pyramidal neurons of 17-month-old mice

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