Involvement of dopaminergic neuronal cystatin C in neuronal injury-induced microglial activation and neurotoxicity

被引:53
作者
Dutta, Garima [1 ]
Barber, David S. [2 ]
Zhang, Ping [1 ]
Doperalski, Nicholas J. [2 ]
Liu, Bin [1 ]
机构
[1] Univ Florida, Coll Pharm, Dept Pharmacodynam, Gainesville, FL 32610 USA
[2] Univ Florida, Coll Vet Med, Dept Physiol Sci, Gainesville, FL 32610 USA
关键词
Caspase; 3; cytokine; dopamine neuron; microglia; nitric oxide; reactive oxygen species; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; PESTICIDE EXPOSURE; PROTEOMIC ANALYSIS; ANIMAL-MODEL; RAT-BRAIN; AGRICULTURAL HEALTH; OXIDATIVE STRESS; NITRIC-OXIDE; CATHEPSIN-B;
D O I
10.1111/j.1471-4159.2012.07826.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
J. Neurochem. (2012) 122, 752763. Abstract Factors released from injured dopaminergic (DA) neurons may trigger microglial activation and set in motion a vicious cycle of neuronal injury and inflammation that fuels progressive DA neurodegeneration in Parkinsons disease. In this study, using proteomic and immunoblotting analysis, we detected elevated levels of cystatin C in conditioned media (CM) from 1-methyl-4-phenylpyridinium and dieldrin-injured rat DA neuronal cells. Immunodepletion of cystatin C significantly reduced the ability of DA neuronal CM to induce activation of rat microglial cells as determined by up-regulation of inducible nitric oxide synthase, production of free radicals and release of proinflammatory cytokines as well as activated microglia-mediated DA neurotoxicity. Treatment of the cystatin C-containing CM with enzymes that remove O- and sialic acid-, but not N-linked carbohydrate moieties markedly reduced the ability of the DA neuronal CM to activate microglia. Taken together, these results suggest that DA neuronal cystatin C plays a role in the neuronal injury-induced microglial activation and neurotoxicity. These findings from the rat DA neuron-microglia in vitro model may help guide continued investigation to define the precise role of cystatin C in the complex interplay among neurons and glia in the pathogenesis of Parkinsons disease.
引用
收藏
页码:752 / 763
页数:12
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