Zuurbier Kielen R, Fonseca Rene Solano, Arneaud Sonja L B, Wall Jordan M, Kim Juhee, Tatge Lexus, Otuzoglu Gupse, Bali Sofia, Metang Patrick, Douglas Peter M
Department of Molecular Biology; University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Nat Commun. 2024 Dec 4;15(1):10592. doi: 10.1038/s41467-024-54958-9.
Neurons deploy diverse adaptive strategies to ensure survival and neurotransmission amid cellular stress. When these adaptive pathways are overwhelmed, functional impairment or neurodegeneration follows. Here we show that stressed neurons actively induce a state of transmissive dormancy as a protective measure. Extending observations of neurotrauma in C. elegans and mice, human dopaminergic neurons capable of surviving severe cellular challenges both decrease spontaneous activity and modulate dopamine homeostasis through the transcriptional regulator Yin Yang 1 (YY1). To bolster stress resilience and mitigate dopamine toxicity, YY1 increases expression of the vesicular monoamine transporter 2, vMAT2, while coordinately inhibiting dopamine synthesis through stabilization of a guanine quadruplex in intron 10 of tyrosine hydroxylase, TH. This dopaminergic stress response has the potential to cause circuit inactivation, yet safeguards neurons by minimizing the toxic accumulation of cytosolic dopamine and inducing a state of neuronal dormancy. In essence, neurons appear to actively prioritize viability over functionality.
神经元会采用多种适应性策略，以确保在细胞应激状态下的存活和神经传递。当这些适应性通路不堪重负时，就会出现功能障碍或神经退行性变。在此，我们表明，应激状态下的神经元会主动诱导一种传导性休眠状态作为保护措施。扩展对秀丽隐杆线虫和小鼠神经创伤的观察结果，能够在严重细胞挑战中存活的人类多巴胺能神经元，会通过转录调节因子阴阳1（YY1）降低自发活动并调节多巴胺稳态。为增强应激恢复力并减轻多巴胺毒性，YY1会增加囊泡单胺转运体2（vMAT2）的表达，同时通过稳定酪氨酸羟化酶（TH）第10内含子中的鸟嘌呤四链体来协同抑制多巴胺合成。这种多巴胺能应激反应有可能导致神经回路失活，但通过将胞质多巴胺的毒性积累降至最低并诱导神经元休眠状态来保护神经元。本质上，神经元似乎会主动将生存能力置于功能之上。
