Pitx3 deficiency promotes age-dependent alterations in striatal medium spiny neurons

Xi Chen; Zhaofei Yang; Yaping Shao; Kunhyok Kim; Yuanyuan Wang; Ying Wang; Haifeng Wu; Xiaolan Xu; Weidong Le

doi:10.3389/fnagi.2022.960479

Pitx3 deficiency promotes age-dependent alterations in striatal medium spiny neurons

Front Aging Neurosci. 2022 Sep 7:14:960479. doi: 10.3389/fnagi.2022.960479. eCollection 2022.

Authors

Xi Chen^{1

2}, Zhaofei Yang³, Yaping Shao³, Kunhyok Kim³, Yuanyuan Wang³, Ying Wang³, Haifeng Wu³, Xiaolan Xu^{1

2}, Weidong Le^{1

2

3}

Affiliations

¹ Institute of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
² Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China.
³ Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, China.

Abstract

Background: 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.

Results: To comprehensively examine pathological alterations of MSNs longitudinally, we established a TH ^Cre/ Pitx3 ^fl/fl (Pitx3^cKO ) 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 Pitx3^cko 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.

Conclusion: 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.

Keywords: DNA methylation; Parkinson’s disease; aging; medium spiny neurons; neuronal morphology.