GADD45G operates as a pathological sensor orchestrating reactive gliosis and neurodegeneration.

IF 14.7 1区 医学 Q1 NEUROSCIENCES
Tianjin Shen, Wenjiao Tai, Dongfang Jiang, Shuaipeng Ma, Xiaoling Zhong, Yuhua Zou, Chun-Li Zhang
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引用次数: 0

Abstract

Reactive gliosis is a hallmark of neuropathology and offers a potential target for addressing numerous neurological diseases. Here, we show that growth arrest and DNA damage inducible gamma (GADD45G), a stress sensor in astrocytes, is a nodal orchestrator of reactive gliosis and neurodegeneration. GADD45G expression in astrocytes is sufficient to incite astrogliosis, microgliosis, synapse loss, compromised animal behavior, and the aggravation of Alzheimer's disease (AD). Conversely, silencing GADD45G specifically in astrocytes preserves synapses and rescues the histological and behavioral phenotypes of AD. Mechanistically, GADD45G controls the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) and neuroimmune signaling pathways, including nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3), leading to profound molecular changes and the secretion of various factors that regulate both cell-autonomous and cell-nonautonomous reactive gliosis and glia-neuron interactions. These results uncover GADD45G signaling as a promising therapeutic target for AD and potentially for numerous other neurological disorders.

GADD45G作为病理传感器协调反应性胶质瘤和神经变性。
反应性神经胶质瘤是神经病理学的标志,并提供了解决许多神经系统疾病的潜在目标。在这里,我们发现生长阻滞和DNA损伤诱导γ (GADD45G),星形胶质细胞中的应激传感器,是反应性胶质瘤和神经变性的节点协调者。GADD45G在星形胶质细胞中的表达足以引发星形胶质细胞增生、小胶质细胞增生、突触丧失、动物行为受损和阿尔茨海默病(AD)的加重。相反,在星形胶质细胞中特异性沉默GADD45G可保留突触并挽救阿尔茨海默病的组织学和行为表型。在机制上,GADD45G控制丝裂原活化蛋白激酶激酶激酶4 (MAP3K4)和神经免疫信号通路,包括核因子κB (NF-κB)和干扰素调节因子3 (IRF3),导致深刻的分子变化和各种因子的分泌,调节细胞自主和细胞非自主反应性胶质瘤和胶质-神经元相互作用。这些结果揭示了GADD45G信号作为阿尔茨海默病和许多其他神经系统疾病的有希望的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neuron
Neuron 医学-神经科学
CiteScore
24.50
自引率
3.10%
发文量
382
审稿时长
1 months
期刊介绍: Established as a highly influential journal in neuroscience, Neuron is widely relied upon in the field. The editors adopt interdisciplinary strategies, integrating biophysical, cellular, developmental, and molecular approaches alongside a systems approach to sensory, motor, and higher-order cognitive functions. Serving as a premier intellectual forum, Neuron holds a prominent position in the entire neuroscience community.
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