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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 1090-2139, Vol. 80, p. 525-535Article in journal (Refereed) Published
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. Vol. 80, p. 525-535
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.2019.04.036ISI: 000478105500051PubMedID: 31029796Scopus ID: 2-s2.0-85064593589OAI: oai:DiVA.org:umu-159474DiVA, id: diva2:1318679
Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2023-03-24Bibliographically approved

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Ådén, JörgenAlmqvist, Fredrik

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