当前位置: X-MOL 学术ASN Neuro › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice
ASN Neuro ( IF 4.7 ) Pub Date : 2021-05-03 , DOI: 10.1177/17590914211009730
Kui Cui 1 , Fan Yang 1, 2 , Turan Tufan 1 , Muhammad U Raza 1 , Yanqiang Zhan 1, 3 , Yan Fan 1, 4 , Fei Zeng 1, 3 , Russell W Brown 1 , Jennifer B Price 5 , Thomas C Jones 5 , Gary W Miller 6 , Meng-Yang Zhu 1
Affiliation  

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.



中文翻译:

帕金森病模型小鼠去甲肾上腺素能功能的恢复

中枢去甲肾上腺素能和多巴胺能系统的功能障碍是帕金森病 (PD) 的主要神经生物学特征。重要的是,发生在 PD 早期的蓝斑 (LC) 中的神经元丢失可能会加速多巴胺能神经元的进行性丢失。因此,恢复缺陷的去甲肾上腺素能系统的活性和功能可能是早期PD的重要治疗策略。在本研究中,转录因子 Phox2a/2b、Hand2 和 Gata3 的慢病毒构建,单独或组合,在 12 和 18 个月大时被显微注射到 PD 模型 VMAT2 Lo 小鼠的 LC 区域。生化分析表明,将慢病毒表达盒显微注射到 LC 中显着增加了 Phox2a 和 Phox2b 的 mRNA 水平,伴随着 LC 中多巴胺 β-羟化酶 (DBH) 和酪氨酸羟化酶 (TH) 的 mRNA 和蛋白质的平行增加。此外,额叶皮层和海马中的 DBH 蛋白水平显着增强,纹状体和黑质中的 TH 蛋白水平也显着增强。此外,这些操作显着增加了纹状体中去甲肾上腺素和多巴胺的浓度,随后显着改善了空间记忆和运动行为。这些结果表明,这些转录因子在 LC 中的过度表达改善了该啮齿动物 PD 模型中的去甲肾上腺素能和多巴胺能活性和功能。它为发展 PD 基因疗法提供了必要的基础,

更新日期:2021-05-04
down
wechat
bug