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

Abstract

BackgroundThe 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.ResultsTo 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.ConclusionThe 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.

The inflammatory injury in the striatal microglia-dopaminergic-neuron crosstalk involved in Tourette syndrome development

“…The PITX3 deficiency can lead to the loss of the substantia nigra striatum path, the deprivation of dopaminergic neurons in the substantia nigra, and the impairment of dopaminergic development, which may drive the development of Parkinson's disease (64). In a TH-Cre/ Pitx3-fl/fl (Pitx3cKO) mouse model, it was noticed that Pitx3 deficiency promotes age-dependent alterations in striatal medium spiny neurons (65). Although many studies have shown the link between PITX3 and Parkinson's disease, the clear association with TS is largely unknown.…”

The Crucial Roles of Pitx3 in Midbrain Dopaminergic Neuron Development and Parkinson’s Disease-Associated Neurodegeneration

“…Meanwhile, the morphologies of medium spiny neurons (MSNs) were altered due to Pitx3 deficiency, including nuclear, soma, and dendritic atrophy, as well as an increased number of nuclear invaginations. Additionally, more nuclear DNA damages were observed in MSNs during aging, while Pitx3-deficiency aggravated this phenomenon, together with alterations of the DNA methylation profiling associated with lipoprotein and nucleus pathways at late stages [42,93], suggesting that early perturbations of neurotransmitters within MSNs may potentially contribute to the alterations of metabolism, morphology, and epigenetics within the striatum at late stages.…”

“…Additionally, given that Pitx3 is an essential transcription factor for mDA development, Pitx3-deficient mice represent a useful tool that permits the study of early events in mDA formation. Moreover, studies have reported that Pitx3 −/− mice produce decreased DA signaling rates and induce motor deficits [92] and can be also used to study the morphological and physiological modulation of striatal neurons [93] even after the administration of L-DOPA or other PD-related drugs [94].…”