Astrocyte inflammatory signaling mediates α-synuclein aggregation and dopaminergic neuronal loss following viral encephalitis

• Published in: Experimental neurology 2021-12, Vol.346, p.113845-113845, Article 113845
• Main Authors: Bantle, Collin M., Rocha, Savannah M., French, C. Tenley, Phillips, Aaron T., Tran, Kevin, Olson, Kenneth E., Bass, Todd A., Aboellail, Tawfik, Smeyne, Richard J., Tjalkens, Ronald B.
• Format: Article
• Language: English
• Subjects: Alpha-synuclein; alpha-Synuclein - metabolism; Alphaviruses; Animals; Astrocytes - immunology; Astrocytes - metabolism; Dopaminergic Neurons - immunology; Dopaminergic Neurons - metabolism; Encephalitis Virus, Western Equine - immunology; Encephalitis Virus, Western Equine - metabolism; Encephalitis, Viral - immunology; Encephalitis, Viral - metabolism; Female; Glia; Humans; Inflammation Mediators - immunology; Inflammation Mediators - metabolism; Male; Mice; Mice, Knockout; Neurodegeneration; Neuroinflammation; Parkinson’s Disease; Protein Aggregates - physiology; Signal Transduction - physiology; Viral encephalitis; Western equine encephalitis virus
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2021.113845

Viral infection of the central nervous system (CNS) can cause lasting neurological decline in surviving patients and can present with symptoms resembling Parkinson's disease (PD). The mechanisms underlying postencephalitic parkinsonism remain unclear but are thought to involve increased innate inflammatory signaling in glial cells, resulting in persistent neuroinflammation. We therefore studied the role of glial cells in regulating neuropathology in postencephalitic parkinsonism by studying the involvement of astrocytes in loss of dopaminergic neurons and aggregation of α–synuclein protein following infection with western equine encephalitis virus (WEEV). Infections were conducted in both wildtype mice and in transgenic mice lacking NFκB inflammatory signaling in astrocytes. For 2 months following WEEV infection, we analyzed glial activation, neuronal loss and protein aggregation across multiple brain regions, including the substantia nigra pars compacta (SNpc). These data revealed that WEEV induces loss of SNpc dopaminergic neurons, persistent activation of microglia and astrocytes that precipitates widespread aggregation of α-synuclein in the brain of C57BL/6 mice. Microgliosis and macrophage infiltration occurred prior to activation of astrocytes and was followed by opsonization of ⍺-synuclein protein aggregates in the cortex, hippocampus and midbrain by the complement protein, C3. Astrocyte-specific NFκB knockout mice had reduced gliosis, α-synuclein aggregate formation and neuronal loss. These data suggest that astrocytes play a critical role in initiating PD-like pathology following encephalitic infection with WEEV through innate immune inflammatory pathways that damage dopaminergic neurons, possibly by hindering clearance of ⍺-synuclein aggregates. Inhibiting glial inflammatory responses could therefore represent a potential therapy strategy for viral parkinsonism. •Infection with WEEV causes dopaminergic neurodegeneration and ⍺-synuclein aggregation in C57Bl/6 mice.•Activation of microglia and astrocytes occurs prior to ⍺-synuclein aggregation and loss of dopamine neurons.•Phenotypic activation of astrocytes to A1 phenotype results in production of complement C3 that opsonizes ⍺-synuclein aggregates.•Cell-specific knockout of NFκB in astrocytes prevents neuroinflammatory activation of microglia and protects against both ⍺-synuclein aggregation and loss of dopamine neurons.