Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling

Zajicek, Alexis S; Ruan, Hongyu; Dai, Huihui; Skolfield, Mary Catherine; Phillips, Hannah; Burnette, Wendi J; Javidfar, Behnam; Sun, Shao‐Cong; Akbarian, Schahram; Yao, Wei‐Dong

doi:10.1038/s41380-022-01571-1

Cited by 15 publications

(10 citation statements)

References 78 publications

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“…In addition, mouse hippocampal neurons transfected with CYLD M719V show a significantly increased cytoplasmic localization of transactivator regulatory DNA-binding protein 43 (TDP-43) and decreased axonal length ( Dobson-Stone et al, 2020 ). CYLD deficiency causes impaired fear memory, auditory neuropathy, and cognitive inflexibility ( Li et al, 2021 ; Yang et al, 2021 ; Zajicek et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum

Tan

Jiang

Huang

et al. 2023

Front. Mol. Neurosci.

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Although the deubiquitinase cylindromatosis (CYLD), an abundant protein in the postsynaptic density fraction, plays a crucial role in mediating the synaptic activity of the striatum, the precise molecular mechanism remains largely unclear. Here, using a Cyld-knockout mouse model, we demonstrate that CYLD regulates dorsolateral striatum (DLS) neuronal morphology, firing activity, excitatory synaptic transmission, and plasticity of striatal medium spiny neurons via, likely, interaction with glutamate receptor 1 (GluA1) and glutamate receptor 2 (GluA2), two key subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). CYLD deficiency reduces levels of GluA1 and GluA2 surface protein and increases K63-linked ubiquitination, resulting in functional impairments both in AMPAR-mediated excitatory postsynaptic currents and in AMPAR-dependent long-term depression. The results demonstrate a functional association of CYLD with AMPAR activity, which strengthens our understanding of the role of CYLD in striatal neuronal activity.

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Section: Introductionmentioning

confidence: 99%

Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum

Tan

Jiang

Huang

et al. 2023

Front. Mol. Neurosci.

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“…Irisin leads to an increase in the activity of protein kinase B (PKB or Akt) in cardiomyoblasts, H9c2 cells, and in endothelial cells and, respectively, to an increase in activity of its downstream mTORC1 and supression of autophagy ( Yang et al, 2013 ; Xie et al, 2015 ; Fu et al, 2016 ; Gao et al, 2021 ; Zajicek et al, 2022 ). Song et al showed that exogenous irisin treatment (50–200 ng/ml, 24–48 h) decreased autophagy in H9c2 cells as it was seen by the decrease in LC3II/LC3I ratio.…”

Section: Autophagy As Targets Of Irisinmentioning

confidence: 99%

Neuroplasticity to autophagy cross-talk in a therapeutic effect of physical exercises and irisin in ADHD

Abdulghani

Poghosyan

Mehren

et al. 2023

Front. Mol. Neurosci.

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“…Akt/mTOR is one of the most widely distributed activators of damage-induced physiological processes. Akt/mTOR activation is closely involved in cell proliferation [ 33 ], migration [ 34 ], differentiation [ 35 ], apoptosis [ 36 ] and autophagy [ 37 ]. Inhibitory factors, including ROS, starvation, hypoxia, inflammation, and other stress conditions, reduce the phosphorylation of PI3K/Akt and the downstream effector mTOR, causing the dysregulation of PI3K/Akt/mTOR-induced cell death and abnormal tissue structure and function [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Adipose-derived stem cells promote the repair of chemotherapy-induced premature ovarian failure by inhibiting granulosa cells apoptosis and senescence

Meng

Guo

et al. 2023

Stem Cell Res Ther

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Background Chemotherapeutic drugs, particularly alkylating cytotoxics such as cyclophosphamide (CTX), play an important role to induce premature ovarian failure (POF). Hormone replacement therapy (HRT) is a widely used treatment to improve hormone secretion. However, the long-term HRT increases the risk of breast cancer and cardiovascular disease are attracting concerns. Therefore, there is an urgent need to develop a safe and effective treatment for POF. Method Adipose-derived stem cells (ADSCs) were isolated and identified from human adipose tissue. For POF modeling, CTX were intraperitoneal injected into CTX-acute group, CTX-chronic group, CTX-acute + ADSCs group and CTX-chronic + ADSCs group rats; For transplantation, ADSCs were transplanted into POF rats through tail-vein. The control group rats were injected with PBS. The effects of POF modeling and transplantation were determined by estrous cycle analysis, histopathological analysis, immunohistochemical staining and apoptosis-related marker. To evaluate the effects of ADSC on granulosa cells in vitro, CTX-induced senescent KGN cells were co-cultured with ADSCs, and senescent-related marker expression was investigated by immunofluorescent staining. Results In vivo studies revealed that ADSCs transplantation reduced the apoptosis of ovarian granulosa cells and secretion of follicle-stimulating hormone. The number of total follicles, primordial follicles, primary follicles, and mature follicles and secretion of anti-Müllerian hormone and estradiol (E2) were also increased by ADSCs. The estrous cycle was also improved by ADSC transplantation. Histopathological analysis showed that CTX-damaged ovarian microenvironment was improved by ADSCs. Furthermore, TUNEL staining indicated that apoptosis of granulosa cells was decreased by ADSCs. In vitro assay also demonstrated that ADSC markedly attenuated CTX-induced senescence and apoptosis of granulosa cell. Mechanistically, both in vivo and in vitro experiments proved that ADSC transplantation suppressed activation of the PI3K/Akt/mTOR axis. Conclusion Our experiment demonstrated that a single injection of high-dose CTX was a less damaging chemotherapeutic strategy than continuous injection of low-dose CTX, and tail-vein injection of ADSCs was a potential approach to promote the restoration of CTX-induced POF.

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Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling

Cited by 15 publications

References 78 publications

Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum

Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum

Neuroplasticity to autophagy cross-talk in a therapeutic effect of physical exercises and irisin in ADHD

Adipose-derived stem cells promote the repair of chemotherapy-induced premature ovarian failure by inhibiting granulosa cells apoptosis and senescence

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