Tau Knockout and α-Synuclein A53T Synergy Modulated Parvalbumin-Positive Neurons Degeneration Staging in Substantia Nigra Pars Reticulata of Parkinson's Disease-Liked Model.

Meige Zheng,Zhaoming Xiao,Yanchang Liu,Xian Lin,Luyan Jiao

doi:10.3389/fnagi.2021.784665

Abstract

The loss of parvalbumin-positive (PV+) neurons in the substantia nigra pars reticulata (SNR) was observed in patients with end-stage Parkinson’s disease (PD) and our previously constructed old-aged Pitx3-A53Tα-Syn × Tau–/– triple transgenic mice model of PD. The aim of this study was to examine the progress of PV+ neurons loss. We demonstrated that, as compared with non-transgenic (nTg) mice, the accumulation of α-synuclein in the SNR of aged Pitx3-A53Tα-Syn × Tau–/– mice was increased obviously, which was accompanied by the considerable degeneration of PV+ neurons and the massive generation of apoptotic NeuN+TUNEL+ co-staining neurons. Interestingly, PV was not costained with TUNEL, a marker of apoptosis. PV+ neurons in the SNR may undergo a transitional stage from decreased expression of PV to increased expression of NeuN and then to TUNEL expression. In addition, the degeneration of PV+ neurons and the expression of NeuN were rarely observed in the SNR of nTg and the other triple transgenic mice. Hence, we propose that Tau knockout and α-syn A53T synergy modulate PV+ neurons degeneration staging in the SNR of aged PD-liked mice model, and NeuN may be suited for an indicator that suggests degeneration of SNR PV+ neurons. However, the molecular mechanism needs to be further investigated.

Highlights

The most predominant pathological feature of Parkinson’s disease (PD) is the massive loss of dopaminergic neurons in the substantial nigra pars compacta (SNC) (Poewe et al, 2017)
We demonstrated that, as compared with non-transgenic mice, the accumulation of α-syn in the substantia nigra pars reticulata (SNR) of aged pituitary homeobox 3 (Pitx3)-A53Tα-Syn × Tau−/− mice was increased obviously, which was accompanied by the considerable loss of PV+ neurons and the massive generation of apoptotic neuronal nucleus (NeuN)+transferase-mediated dUTP nick end labeling (TUNEL)+ neurons
The results showed that compared with nTg mice, α-syn was significantly overexpressed in the SNC of all triple transgenic mice, as expected (Figure 1A)

Summary

Introduction

The most predominant pathological feature of Parkinson’s disease (PD) is the massive loss of dopaminergic neurons in the substantial nigra pars compacta (SNC) (Poewe et al, 2017). Previous studies showed that the activity of parvalbumin-positive (PV+) neurons in the SNR were affected in PD animal models (Wichmann et al, 1999; Mallet et al, 2019; Pamukcu et al, 2020). Our previous study found that the Pitx3-A53Tα-Syn × Tau−/− triple transgenic mice model of PD showed anxiety-like behavior among 12- to 18-mouth-old, which may be related to the substantial degeneration of PV+ neurons in the SNR (Jiao et al, 2020). The progress and stage marker of PV+ neurons loss are still unclear

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