NR4A2(NURR1)旁系亲属在斑马鱼大脑和行为中的不同作用。

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Michael Kalyn, Rose Garvey, Hyojin Lee, Herman Aishi Mbesha, Jory Curry, Vishal Saxena, Jan A Mennigen, Marc Ekker
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引用次数: 0

摘要

多巴胺能(DAnergic)功能障碍和多巴胺(DA)水平失衡是众多精神疾病和神经退行性疾病的已知致病因素。在许多已确定的多巴胺相关疾病的风险因素中,核受体亚家族 4 A2 组(NR4A2;或核受体相关-1 蛋白(NURR1))是一种参与多巴胺能分化的转录因子,它与帕金森病和注意力缺陷多动障碍(ADHD)有关。在斑马鱼中,nr4a2 的瞬时缺失曾被证明会降低酪氨酸羟化酶(TH)的表达并损害运动能力。为了进一步确定两种斑马鱼 nr4a2 旁系亲属(nr4a2a 和 nr4a2b)的作用,我们制造了靶向功能缺失突变体,并研究了 DAnergic 神经元再生、氧化呼吸和行为特征。nr4a2a功能缺失更接近帕金森病表型,并影响神经营养因子基因的表达。相反,nr4a2b 突变体的行为症状与 Nr4a2 缺失的小鼠相似,但神经营养输出增加。相反,nr4a2b 突变体还显示出非线粒体来源的代谢输入增加,表明细胞膜活性氧含量高,线粒体功能紊乱。nr4a2a 突变体的最大呼吸量也有所增加,这可能表明这是一种补偿机制,以满足神经元健康的代谢要求。总之,本研究中产生的斑马鱼突变体有助于发现DA相关疾病病理和DA能神经元再生的分子机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Differential roles of NR4A2 (NURR1) paralogs in the brain and behavior of zebrafish.

Dopaminergic (DAnergic) dysfunction and imbalanced dopamine (DA) levels are known contributors to the pathogenesis of numerous psychiatric and neurodegenerative disorders. Of the many identified risk factors for DA-associated disorders, nuclear receptor subfamily 4 group A2 (NR4A2; or nuclear receptor related-1 protein (NURR1)), a transcription factor involved in DAnergic differentiation, has been associated with Parkinson's disease and attention deficit hyperactive disorder (ADHD). In zebrafish, transient loss of nr4a2 was previously shown to decrease tyrosine hydroxylase (TH) expression and impair locomotion. To further characterize the roles of the two zebrafish nr4a2 paralogs, nr4a2a, and nr4a2b, we produced targeted loss-of-function mutants and examined DAnergic neuron regeneration, oxidative respiration, and behavioral traits. The loss of nr4a2a function more closely recapitulated Parkinsonian phenotypes and affected neurotrophic factor gene expression. Conversely, nr4a2b mutants displayed behavioral symptoms reminiscent of mice deficient in Nr4a2 with increased neurotrophic output. In contrast, nr4a2b mutants also displayed increased metabolic input from non-mitochondrial sources indicative of high cytosolic reactive oxygen species and perturbed mitochondrial function. The nr4a2a mutants also showed increased maximal respiration, which may suggest a compensatory mechanism to meet the metabolic requirements of DAnergic neuron health. Overall, the zebrafish mutants generated in this study helped uncover molecular mechanisms involved in DA-related disease pathologies, and in the regeneration of DAnergic neurons.

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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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