Genetic and Pharmacological Inhibition of Astrocytic Mysm1 Alleviates Depressive‐Like Disorders by Promoting ATP Production

Zhang, Heyang; Liu, Shuirong; Qin, Qiaozhen; Xu, Zhenhua; Qu, Yannv; Wang, Yadi; Wang, Jianbo; Du, Zhangzhen; Yuan, Shanshan; Hong, Shunming; Chang, Zhilin; He, Wenyan; Yan, Xinlong; Lang, Yiran; Tang, Rongyu; Wang, Yan; Zhu, Ling‐Ling; Jiang, Xiaoxia

doi:10.1002/advs.202204463

Cited by 4 publications

(4 citation statements)

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“…Mysm1 has been reported to play important roles in many cells, such as HSCs, MSCs, immune cells, and astrocytes [ 13 , 14 , 16 , 19 , 21 ]. Here, we found that Mysm1 was expressed in Nestin-positive NSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Bahrami et al reported that two patients with Mysm1 deficiency show neurocognitive developmental delay [ 22 ]. Our previous research revealed the important function of Mysm1 in the brain, highlighting astrocytic Mysm1 as a potential risk factor for depression and as a valuable target for drug discovery to treat depression [ 16 ]. Considering the important role of Mysm1 in stem cell homeostasis and brain function, we hypothesized that Mysm1 may regulate NSC homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression

Xu,

Qin,

Wang

et al. 2024

Cell Death Dis

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Neural stem cells (NSCs) are critical for brain development and maintenance of neurogenesis. However, the molecular mechanisms that regulate NSC proliferation and differentiation remain unclear. Mysm1 is a deubiquitinase and is essential for the self-renewal and differentiation of several stem cells. It is unknown whether Mysm1 plays an important role in NSCs. Here, we found that Mysm1 was expressed in NSCs and its expression was increased with age in mice. Mice with Mysm1 knockdown by crossing Mysm1 floxed mice with Nestin-Cre mice exhibited abnormal brain development with microcephaly. Mysm1 deletion promoted NSC proliferation and apoptosis, resulting in depletion of the stem cell pool. In addition, Mysm1-deficient NSCs skewed toward neurogenesis instead of astrogliogenesis. Mechanistic investigations with RNA sequencing and genome-wide CUT&Tag analysis revealed that Mysm1 epigenetically regulated Id4 transcription by regulating histone modification at the promoter region. After rescuing the expression of Id4, the hyperproliferation and imbalance differentiation of Mysm1-deficient NSCs was reversed. Additionally, knockdown Mysm1 in aged mice could promote NSC proliferation. Collectively, the present study identified a new factor Mysm1 which is essential for NSC homeostasis and Mysm1-Id4 axis may be an ideal target for proper NSC proliferation and differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression

Xu,

Qin,

Wang

et al. 2024

Cell Death Dis

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“…Zhang et al. reported that genetic and pharmacological inhibition of astrocytic mysm1 could alleviate depressive‐like disorders by promoting ATP production and ATP release through the p53‐AMPK‐Sirt1‐PGC1α (p53, a kind of tumor suppressor gene; AMPK, AMP activates protein kinase; Sirt1, silent mating type information regulation 2 homolog‐1; PGC1α, peroxisome proliferators‐activated receptor γ coactivator l α) pathway 70 . Lu et al.…”

Section: Neurological Mechanism Of Eatp In Depressionmentioning

confidence: 99%

“…reported that genetic and pharmacological inhibition of astrocytic mysm1 could alleviate depressive‐like disorders by promoting ATP production and ATP release through the p53‐AMPK‐Sirt1‐PGC1α (p53, a kind of tumor suppressor gene; AMPK, AMP activates protein kinase; Sirt1, silent mating type information regulation 2 homolog‐1; PGC1α, peroxisome proliferators‐activated receptor γ coactivator l α) pathway. 70 Lu et al. discovered that the reduction in astrocytic glucocorticoid receptors leads to decreased ATP release, resulting in depressive‐like behaviors, and this effect is mediated by the PI3K‐AKT (PI3K, Phosphatidylinositol3‐kinase; AKT/PKB, protein kinase B) signaling pathway.…”

Section: Neurological Mechanism Of Eatp In Depressionmentioning

confidence: 99%

The neurobiological mechanisms and therapeutic prospect of extracellular ATP in depression

Wang,

Huang,

et al. 2024

CNS Neurosci Ther

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BackgroundDepression is a prevalent psychiatric disorder with high long‐term morbidities, recurrences, and mortalities. Despite extensive research efforts spanning decades, the cellular and molecular mechanisms of depression remain largely unknown. What's more, about one third of patients do not have effective anti‐depressant therapies, so there is an urgent need to uncover more mechanisms to guide the development of novel therapeutic strategies. Adenosine triphosphate (ATP) plays an important role in maintaining ion gradients essential for neuronal activities, as well as in the transport and release of neurotransmitters. Additionally, ATP could also participate in signaling pathways following the activation of postsynaptic receptors. By searching the website PubMed for articles about “ATP and depression” especially focusing on the role of extracellular ATP (eATP) in depression in the last 5 years, we found that numerous studies have implied that the insufficient ATP release from astrocytes could lead to depression and exogenous supply of eATP or endogenously stimulating the release of ATP from astrocytes could alleviate depression, highlighting the potential therapeutic role of eATP in alleviating depression.AimCurrently, there are few reviews discussing the relationship between eATP and depression. Therefore, the aim of our review is to conclude the role of eATP in depression, especially focusing on the evidence and mechanisms of eATP in alleviating depression.ConclusionWe will provide insights into the prospects of leveraging eATP as a novel avenue for the treatment of depression.

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Genetic and Pharmacological Inhibition of Astrocytic Mysm1 Alleviates Depressive‐Like Disorders by Promoting ATP Production

et al. 2022

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Major depressive disorder (MDD) is a leading cause of disability worldwide. A comprehensive understanding of the molecular mechanisms of this disorder is critical for the therapy of MDD. In this study, it is observed that deubiquitinase Mysm1 is induced in the brain tissues from patients with major depression and from mice with depressive behaviors. The genetic silencing of astrocytic Mysm1 induced an antidepressant‐like effect and alleviated the osteoporosis of depressive mice. Furthermore, it is found that Mysm1 knockdown led to increased ATP production and the activation of p53 and AMP‐activated protein kinase (AMPK). Pifithrin α (PFT α) and Compound C, antagonists of p53 and AMPK, respectively, repressed ATP production and reversed the antidepressant effect of Mysm1 knockdown. Moreover, the pharmacological inhibition of astrocytic Mysm1 by aspirin relieved depressive‐like behaviors in mice. The study reveals, for the first time, the important function of Mysm1 in the brain, highlighting astrocytic Mysm1 as a potential risk factor for depression and as a valuable target for drug discovery to treat depression.

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Genetic and Pharmacological Inhibition of Astrocytic Mysm1 Alleviates Depressive‐Like Disorders by Promoting ATP Production

Cited by 4 publications

References 65 publications

Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression

Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression

The neurobiological mechanisms and therapeutic prospect of extracellular ATP in depression

Genetic and Pharmacological Inhibition of Astrocytic Mysm1 Alleviates Depressive‐Like Disorders by Promoting ATP Production

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