Microglia activation-induced mesencephalic dopaminergic neurodegeneration--- an <italic>in vitro</italic> model for Parkinson’s disease

doi:10.1007/s11515-012-1239-6

Front Biol

2012, Vol. 7

Issue (5) : 404-411 https://doi.org/10.1007/s11515-012-1239-6

REVIEW

Microglia activation-induced mesencephalic dopaminergic neurodegeneration--- an in vitro model for Parkinson’s disease

Bin XING¹, Guoying BING²(

)

1. Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; 2. Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536, USA

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Abstract

Uncontrolled and chronic microglia activation has been implicated in the process of dopaminergic neuron degeneration in sporadic Parkinson’s disease (PD). Elevated proinflammatory mediators, presumably from activated microglia (e.g., cytokines, PGE₂, nitric oxide, and superoxide radical), have been observed in PD patients and are accompanied by dopaminergic neuronal loss. Preclinical studies have demonstrated the deleterious effects of proinflammatory mediators in various in vivo and in vitro models of PD. The use of in vitro studies provides a unique tool to investigate the interaction between neurons and microglia and is especially valuable when considering the role of activated microglia in neuronal death. Here we summarize findings highlighting the potential mechanisms of microglia-mediated neurodegeneration in PD.

Keywords dopaminergic neurons microglia activation nitric oxide cytokines PGE₂ p38 MAPK

Corresponding Author(s): BING Guoying,Email:gbing@uky.edu

Issue Date: 01 October 2012

Cite this article:

Guoying BING,Bin XING. Microglia activation-induced mesencephalic dopaminergic neurodegeneration--- an in vitro model for Parkinson’s disease[J]. Front Biol, 2012, 7(5): 404-411.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-012-1239-6
https://academic.hep.com.cn/fib/EN/Y2012/V7/I5/404

Fig.1 Schematic summary of the key molecules and their signaling cascades in the activated microglia and dopaminergic neuron. Upon the stimuli from LPS or other extracellular molecules such as HMGB1 and ones released from injured neurons such as α-synuclein, microglia are activated and release PHOX-mediated free radicals such as superoxide, and MAPKs signaling-mediated production of nitric oxide, progstagland E2, and cytokines such as TNFα. The superoxide and nitric oxide can readily react and form highly diffusible cytoxic molecules peroxynitrite (ONOO-), which can direclty cause the nitration of the key proteins such as α-synuclein and lead to its aggregation, causing neuronal apoptosis probably via inhibiting the function of ubiqutin proteasome system. In addition, ONOO- can react with mitochondrial membrane and cause its dysfunction via inhibition of complex I, enhancing the intracellular burden of oxidative stress. Microglia-derived PGE induces neuronal death via its receptor EP1, though no downstream signaling has been studied in the neurons. Upon binding to its TNFR1 receptor, the overwhelming signaling from TNFα may initiate the activation of proinflammatory signaling such as p38 MAPK, leading to the activation of caspases signaling, ultimately leading to neuronal apoptosis.

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