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Chronic Corticosterone Elevation Suppresses Adult Hippocampal Neurogenesis by Hyperphosphorylating Huntingtin.
Cell Reports ( IF 8.8 ) Pub Date : 2020-07-07 , DOI: 10.1016/j.celrep.2020.107865
Fabienne Agasse 1 , Indira Mendez-David 2 , Wilhelm Christaller 1 , Rémi Carpentier 1 , Barbara Y Braz 1 , Denis J David 2 , Frédéric Saudou 1 , Sandrine Humbert 1
Affiliation  

Chronic exposure to stress is a major risk factor for neuropsychiatric disease, and elevated plasma corticosterone (CORT) correlates with reduced levels of both brain-derived neurotrophic factor (BDNF) and hippocampal neurogenesis. Precisely how these phenomena are linked, however, remains unclear. Using a cortico-hippocampal network-on-a-chip, we find that the glucocorticoid receptor agonist dexamethasone (DXM) stimulates the cyclin-dependent kinase 5 (CDK5) to phosphorylate huntingtin (HTT) at serines 1181 and 1201 (S1181/1201), which retards BDNF vesicular transport in cortical axons. Parallel studies in mice show that CORT induces phosphorylation of these same residues, reduces BDNF levels, and suppresses neurogenesis. The adverse effects of CORT are reduced in mice bearing an unphosphorylatable mutant HTT (HdhS1181A/S1201A). The protective effect of unphosphorylatable HTT, however, disappears if neurogenesis is blocked. The CDK5-HTT pathway, which regulates BDNF transport in the cortico-hippocampal network, thus provides a missing link between elevated CORT levels and suppressed neurogenesis.



中文翻译:

慢性皮质激素升高通过亨廷顿蛋白的过度磷酸化抑制成人海马神经发生。

长期暴露于压力是神经精神疾病的主要危险因素,血浆皮质酮(CORT)升高与脑源性神经营养因子(BDNF)和海马神经发生水平降低有关。究竟这些现象如何关联尚不清楚。使用皮质-海马芯片网络,我们发现糖皮质激素受体激动剂地塞米松(DXM)刺激细胞周期蛋白依赖性激酶5(CDK5)磷酸化丝氨酸1181和1201处的亨廷顿蛋白(HTT)(S1181 / 1201) ,这会延迟BDNF在皮质轴突中的囊泡运输。小鼠的平行研究表明,CORT可以诱导这些相同残基的磷酸化,降低BDNF的水平,并抑制神经发生。携带不可磷酸化突变体HTT(HdhS1181A / S1201A)。但是,如果神经发生受阻,不可磷酸化的HTT的保护作用就会消失。CDK5-HTT通路调节皮质海马网络中的BDNF转运,因此在CORT水平升高和神经发生抑制之间提供了缺失的联系。

更新日期:2020-07-07
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