Viral mimetic priming enhances α-synuclein-induced degeneration: Implications for Parkinson's disease

Laura K. Olsen, Andrew G. Cairns, Jörgen Ådén, Niamh Moriarty, Silvia Cabre, Veronica R. Alamilla, Fredrik Almqvist, Eilís Dowd, Declan P. McKernan (Lead / Corresponding author)

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Abstract

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.

Original languageEnglish
Pages (from-to)525-535
Number of pages11
JournalBrain, Behavior, and Immunity
Volume80
Early online date25 Apr 2019
DOIs
Publication statusPublished - Aug 2019

Keywords

  • Neurodegeneration
  • Neuroinflammation
  • Parkinson's disease
  • Viral infection
  • α-Synuclein

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    Olsen, L. K., Cairns, A. G., Ådén, J., Moriarty, N., Cabre, S., Alamilla, V. R., Almqvist, F., Dowd, E., & McKernan, D. P. (2019). Viral mimetic priming enhances α-synuclein-induced degeneration: Implications for Parkinson's disease. Brain, Behavior, and Immunity, 80, 525-535. https://doi.org/10.1016/j.bbi.2019.04.036