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

Brain Behav Immun. 2019 Aug;80:525-535. doi: 10.1016/j.bbi.2019.04.036. Epub 2019 Apr 25.

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.

Keywords: Neurodegeneration; Neuroinflammation; Parkinson’s disease; Viral infection; α-Synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomimetic Materials
  • Corpus Striatum / metabolism
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genetic Vectors
  • Gliosis / metabolism
  • Male
  • Motor Activity / drug effects
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / physiopathology
  • Neuroimmunomodulation / physiology
  • Neurons / metabolism
  • Parkinson Disease / etiology*
  • Parkinson Disease / metabolism
  • Parkinson Disease / physiopathology
  • Poly I-C / administration & dosage
  • Poly I-C / adverse effects*
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / virology
  • Rats
  • Rats, Sprague-Dawley
  • Substantia Nigra / metabolism
  • Tyrosine 3-Monooxygenase / metabolism
  • alpha-Synuclein / metabolism*
  • alpha-Synuclein / physiology

Substances

  • alpha-Synuclein
  • Tyrosine 3-Monooxygenase
  • Poly I-C