Pitx3 deficiency promotes age-dependent alterations in striatal medium spiny neurons.
Pitx3 deficiency promotes age-dependent alterations in striatal medium spiny neurons.
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Pitx3缺陷促进纹状体中棘神经元的年龄依赖性改变
DOI：
10.3389/fnagi.2022.960479
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发表时间：
2022
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
帕金森氏病(PD)的经典运动症状与纹状体内多巴胺的逐渐丧失密切相关。相伴而来的是，中棘神经元(MSN)也经历了形态变化，例如树突复杂性和棘密度降低，这可能也与运动功能障碍有关。因此，除中脑多巴胺能神经元外，MSN可能成为帕金森病治疗的新靶点。为了全面研究MSN的纵向病理改变，我们建立了一种THCre/Pitx3fl/fl(Pitx3cKO)小鼠模型，该模型表现出典型的帕金森病特征，包括黑质神经元的显著丢失和运动障碍。在衰老过程中，由于Pitx3缺乏，靶向神经递质、MSN形态和DNA甲基化特征显著改变。具体地说，在模型的早期阶段，多巴胺、GABA和谷氨酸减少。而在衰老的Pitx3cko小鼠MSN中，核、胞体和树突萎缩以及核内陷增加。此外，在衰老过程中，MSN表现出更多的核DNA损伤，而Pitx3缺乏加剧了这一现象，并在晚期与脂蛋白和核途径相关的DNA甲基化改变。早期MSN内神经递质的紊乱可能导致晚期纹状体内代谢、形态和表观遗传学的改变，这可能为PD的诊断和发病机制提供新的视角。
The classical motor symptoms of Parkinson’s disease (PD) are tightly linked to the gradual loss of dopamine within the striatum. Concomitantly, medium spiny neurons (MSNs) also experience morphological changes, such as reduced dendritic complexity and spine density, which may be potentially associated with motor dysfunction as well. Thus, MSNs may serve as the emerging targets for PD therapy besides the midbrain dopaminergic neurons. To comprehensively examine pathological alterations of MSNs longitudinally, we established a THCre/Pitx3fl/fl (Pitx3cKO) mouse model that developed canonical PD features, including a significant loss of SNc DAergic neurons and motor deficits. During aging, the targeted neurotransmitter, MSNs morphology and DNA methylation profile were significantly altered upon Pitx3 deficiency. Specifically, dopamine, GABA and glutamate decreased in the model at the early stage. While nuclear, soma and dendritic atrophy, as well as nuclear invaginations increased in the aged MSNs of Pitx3cko mice. Furthermore, more nuclear DNA damages were characterized in MSNs during aging, and Pitx3 deficiency aggravated this phenomenon, together with alterations of DNA methylation profiling associated with lipoprotein and nucleus pathway at the late stage. The early perturbations of the neurotransmitters within MSNs may potentially contribute to the alterations of metabolism, morphology and epigenetics within the striatum at the late stage, which may provide new perspectives on the diagnosis and pathogenesis of PD.
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影响因子：
5.3
作者：
Jamwal S;Kumar P
通讯作者：
Kumar P
影响因子：
2.5
作者：
Filipovic, Marko;Ketzef, Maya;Kumar, Arvind
通讯作者：
Kumar, Arvind
影响因子：
4.8
作者：
Miranda-Morales E;Meier K;Sandoval-Carrillo A;Salas-Pacheco J;Vázquez-Cárdenas P;Arias-Carrión O
通讯作者：
Arias-Carrión O
影响因子：
64.8
作者：
Liu, Guang-Hui;Qu, Jing;Suzuki, Keiichiro;Nivet, Emmanuel;Li, Mo;Montserrat, Nuria;Yi, Fei;Xu, Xiuling;Ruiz, Sergio;Zhang, Weiqi;Wagner, Ulrich;Kim, Audrey;Ren, Bing;Li, Ying;Goebl, April;Kim, Jessica;Soligalla, Rupa Devi;Dubova, Ilir;Thompson, James;Yates, John, III;Esteban, Concepcion Rodriguez;Sancho-Martinez, Ignacio;Izpisua Belmonte, Juan Carlos
通讯作者：
Izpisua Belmonte, Juan Carlos
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.