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Viral mimetic priming enhances α-synuclein-induced degeneration: implications for Parkinson's disease
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2019 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139Article in journal (Refereed) Epub ahead of print
Abstract [en]

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 α-synuclein 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 α-synuclein aggregation in the context of Parkinson’s disease, this study sought to determine the impact of viral neuroinflammatory priming on α-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 α-synuclein fibril formation (FN075). The impact of the viral priming on α-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 α-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 α-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson’s disease.

Place, publisher, year, edition, pages
Elsevier, 2019.
Keywords [en]
Parkinson’s disease, Viral infection, Neuroinflammation, α-Synuclein, Neurodegeneration
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-159474DOI: 10.1016/j.bbi.2019.04.036OAI: oai:DiVA.org:umu-159474DiVA, id: diva2:1318679
Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2019-06-20

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Ådén, JörgenAlmqvist, Fredrik

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