TrkB signaling regulates the cold-shock protein RBM3-mediated neuroprotection.
TrkB signaling regulates the cold-shock protein RBM3-mediated neuroprotection.
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DOI：
10.26508/lsa.202000884
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发表时间：
2021-04
影响因子：
4.4
通讯作者：
Mallucci GR
中科院分区：
文献类型：
--
作者：
Peretti D;Smith HL;Verity N;Humoud I;de Weerd L;Swinden DP;Hayes J;Mallucci GR
冷休克蛋白RBM3的神经保护作用对治疗具有广泛的吸引力。通过冷却的RBM3诱导通过TrkB信号传导的非典型模式发生。现在，该通路可以靶向RBM3介导的神经保护作用，而无需冷却。通过冷却或异位过表达增加冷休克蛋白RNA结合基序3（RBM3）的水平，可以防止神经退行性变小鼠模型中的突触和神经元丢失。为了在治疗上利用这一过程，需要了解控制冷诱导的RBM3表达的机制。在这里，我们表明冷却通过PLCγ1和pCREB信号转导激活TrkB来增加RBM3。反过来，RBM3通过诱导其特异性磷酸酶DUSP6对TrkB诱导的ERK活化具有迄今未被认识的负反馈。因此，RBM3通过TrkB信号传导的独特的、非典型的激活来介导结构可塑性，这在RBM3缺失的神经元中被消除。TrkB及其下游介质的遗传减少和药理学拮抗作用都消除了冷却诱导的RBM3诱导并阻止结构可塑性，而TrkB抑制类似地阻止了RBM3诱导和朊病毒病小鼠中冷却的神经保护作用。相反，TrkB激动诱导RBM3而不冷却，防止突触丢失和神经变性。因此，TrkB信号传导对于诱导RBM3和相关的神经保护作用是必需的，并且提供了一种靶标，通过该靶标，可以在治疗上使用神经退行性疾病中的RBM3介导的突触再生疗法，而不需要诱导低温。
The neuroprotective effects of the cold-shock protein RBM3 have broad appeal for therapy. RBM3 induction through cooling occurs through a non-canonical pattern of TrkB signaling. The pathway can now be targeted pharmacologically for RBM3-mediated neuroprotection without the need for cooling. Increasing levels of the cold-shock protein, RNA-binding motif 3 (RBM3), either through cooling or by ectopic over-expression, prevents synapse and neuronal loss in mouse models of neurodegeneration. To exploit this process therapeutically requires an understanding of mechanisms controlling cold-induced RBM3 expression. Here, we show that cooling increases RBM3 through activation of TrkB via PLCγ1 and pCREB signaling. RBM3, in turn, has a hitherto unrecognized negative feedback on TrkB-induced ERK activation through induction of its specific phosphatase, DUSP6. Thus, RBM3 mediates structural plasticity through a distinct, non-canonical activation of TrkB signaling, which is abolished in RBM3-null neurons. Both genetic reduction and pharmacological antagonism of TrkB and its downstream mediators abrogate cooling-induced RBM3 induction and prevent structural plasticity, whereas TrkB inhibition similarly prevents RBM3 induction and the neuroprotective effects of cooling in prion-diseased mice. Conversely, TrkB agonism induces RBM3 without cooling, preventing synapse loss and neurodegeneration. TrkB signaling is, therefore, necessary for the induction of RBM3 and related neuroprotective effects and provides a target by which RBM3-mediated synapse-regenerative therapies in neurodegenerative disorders can be used therapeutically without the need for inducing hypothermia.
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DOI：
10.1016/j.cub.2017.01.047
发表时间：
2017-03-06
期刊：
Current biology : CB
影响因子：
--
作者：
Bastide A;Peretti D;Knight JR;Grosso S;Spriggs RV;Pichon X;Sbarrato T;Roobol A;Roobol J;Vito D;Bushell M;von der Haar T;Smales CM;Mallucci GR;Willis AE
通讯作者：
Willis AE
影响因子：
14.8
作者：
Beaudoin, Gerard M. J., III;Lee, Seung-Hye;Arikkath, Jyothi
通讯作者：
Arikkath, Jyothi
DOI：
10.1073/pnas.0912973107
发表时间：
2010-04-13
影响因子：
11.1
作者：
Chen, Lulu Y.;Rex, Christopher S.;Gall, Christine M.
通讯作者：
Gall, Christine M.
影响因子：
2
作者：
Alonso, M;Medina, JH;Pozzo-Miller, L
通讯作者：
Pozzo-Miller, L
冷应激蛋白RBM3在年轻神经元中以超敏感的方式对温度的变化做出反应。
影响因子：
3.3
作者：
Jackson TC;Manole MD;Kotermanski SE;Jackson EK;Clark RS;Kochanek PM
通讯作者：
Kochanek PM