Temporal Evolution of Inflammation and Neurodegeneration With Alpha-Synuclein Propagation in Parkinson's Disease Mouse Model.

Thuy Thi Lai,Phuong Thi Nguyen,Hyeo-Il Ma,Yun Joong Kim,Tinh Thi Nguyen,Young Ho Koh,Young Eun Kim

doi:10.3389/fnint.2021.715190

Abstract

According to a few studies, α-synuclein (αSyn) propagation has been suggested to play a key role in the pathomechanism of Parkinson's disease (PD), but neurodegeneration and the involvement of inflammation in its pathologic progression are not well understood with regard to temporal relationship. In this study, with the help of the PD mouse model injected with intrastriatal αSyn preformed fibril (PFF), the temporal evolution of αSyn propagation, inflammation, and neurodegeneration was explored in the perspective of the striatum and the whole brain. In the PFF-injected striatum, inflammatory response cells, including microglia and astrocytes, were activated at the earliest stage and reduced with time, and the phosphorylated form of αSyn accumulation increased behind it. Afterward, the degeneration of striatal dopaminergic neurons became significant with the conspicuity of behavioral phenotype. Similar patterns of forefront eruption of inflammation and then followed by αSyn propagation were noted in the opposite striatum, which were not injured by PFF injection. In analyzing the whole brain, inflammatory responses were activated at the earliest stage, and the soluble αSyn expression increased concurrently. The inflammatory response decreased afterward, and the accumulation of the insoluble form of αSyn increased behind it. Our results suggested that the inflammatory response may precede the accumulation of the pathologic form of αSyn; thereafter, the neurodegeneration and motor dysfunction followed αSyn proliferation in the PD mouse model. From this model, recognizing the temporal relationship between inflammation, αSyn propagation, and neurodegeneration may be helpful in establishing the PD animal model and monitoring the effect of interventional therapy.

Highlights

Parkinson’s disease (PD), which has been considered as the second most common neurodegenerative disease, is characterized by a profound loss of nigrostriatal dopaminergic neurons and its relevant clinical features of Parkinsonism— bradykinesia, rigidity, gait disturbance, and tremor (Kouli et al, 2018)
This study suggests that the inflammatory response, especially microglia, may precede the accumulation and propagation of αSyn after preformed fibril (PFF) injection; thereafter, neurodegeneration and parkinsonian clinical features were noted in the PD mouse model following αSyn proliferation
This study demonstrated the temporal relationship of inflammatory responses, αSyn propagation, and neurodegeneration in the PFF-injected PD mouse model

Summary

Introduction

Parkinson’s disease (PD), which has been considered as the second most common neurodegenerative disease, is characterized by a profound loss of nigrostriatal dopaminergic neurons and its relevant clinical features of Parkinsonism— bradykinesia, rigidity, gait disturbance, and tremor (Kouli et al, 2018). In addition to αSyn propagation, neuroinflammation has been suggested as one of the main mechanisms contributing to PD pathogenesis (Harms et al, 2020; Hirsch and Standaert, 2020). Astrocytic activation, and increased MHC-II, MHC-I expression has been reported to contribute to the progression of PD (Choi et al, 2020; Rostami et al, 2020). In another aspect, the neuroprotective function of microglia in the αSyn transmission was proposed (Xia et al, 2019). The precise role of inflammation in this αSyn-associated disease process is not fully understood, inflammation may be not just the result of the disease process but may be the contributor in the progressive nature of synucleinopathy (Xia et al, 2019; Brás et al, 2020; Guo et al, 2020; Harms et al, 2020; Hirsch and Standaert, 2020)

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Conclusion