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Olsen, LK,Cairns, AG,Aden, J,Moriarty, N,Cabre, S,Alamilla, VR,Almqvist, F,Dowd, E,McKernan, DP
2019
August
Brain Behavior And Immunity
Viral mimetic priming enhances alpha-synuclein-induced degeneration: Implications for Parkinson's disease
Published
Optional Fields
Parkinson's disease Viral infection Neuroinflammation alpha-Synuclein Neurodegeneration CENTRAL-NERVOUS-SYSTEM TOLL-LIKE RECEPTOR-3 NF-KAPPA-B HERPES-SIMPLEX RAT MODELS MOVEMENT-DISORDERS VIRUS-ANTIBODIES ACTIVATION AUTOPHAGY INFECTION
80
525
535
Evidence is accumulating to suggest that viral infections and consequent viral-mediated neuroinflammation may contribute to the etiology of idiopathic Parkinson's disease. Moreover, viruses have been shown to influence asynuclein oligomerization as well as the autophagic clearance of abnormal intra-cellular proteins aggregations, both of which are key neuropathological events in Parkinson's disease pathogenesis. To further investigate the interaction between viral-mediated neuroinflammation and alpha-synuclein aggregation in the context of Parkinson's disease, this study sought to determine the impact of viral neuroinflammatory priming on alpha-synuclein aggregate-induced neuroinflammation and neurotoxicity in the rat nigrostriatal pathway. To do so, male Sprague-Dawley rats were intra-nigrally injected with a synthetic mimetic of viral dsRNA (poly I:C) followed two weeks later by a peptidomimetic small molecule which accelerates alpha-synuclein fibril formation (FN075). The impact of the viral priming on alpha-synuclein aggregation-induced neuroinflammation, neurodegeneration and motor dysfunction was assessed. We found that prior administration of the viral mimetic poly I:C significantly exacerbated or precipitated the alpha-synuclein aggregate induced neuropathological and behavioral effects. Specifically, sequential exposure to the two challenges caused a significant increase in nigral microgliosis (p < 0.001) and astrocytosis (p < 0.01); precipitated a significant degeneration of the nigrostriatal cell bodies (p < 0.05); and precipitated a significant impairment in forelimb kinesis (p < 0.01) and sensorimotor integration (p < 0.01). The enhanced sensitivity of the nigrostriatal neurons to pathological alpha-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson's disease.
10.1016/j.bbi.2019.04.036
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