Sequential exposure to manganese and encephalitic viral infection causes a Parkinsonian phenotype likely mediated by astrogliosis
Date
2021
Authors
Hampton, Lucas, author
Wilusz, Carol, advisor
Vigh, Jozsef, committee member
Bouma, Gerrit, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
Developmental exposure to environmental toxins increases neuronal susceptibility to injury from subsequent viral challenges. Neurodegenerative diseases such as Parkinson's Disease (PD) present with a neuroinflammatory component often linked to environmental risk factors— including toxic metals, chemicals, physical injury, and viral infection. While many of these risk factors are sufficient to cause a Parkinsonian disease state, none have been shown to be necessary, suggesting an underlying shared mechanism. Furthermore, for any individual risk factor, there is high variability regarding development and severity of the disease. One way to address these issues employs multiple risk factors to model the disease more accurately, although it is unclear how or why multiple unrelated insults have a compounding effect. Neuroinflammation is a shared consequence of the known environmental risk factors. Increased susceptibility to one insult following a challenge with another environmental toxicant may therefore be mediated by neuroinflammatory signaling cascades, a process largely regulated by glial cells, primarily astrocytes. Reactive astrocytes produce neuroinflammatory cytokines, the expression of which is governed by the transcription factor complex NF-κB, and its regulatory kinase, IKK2. The current study uses a two-hit model of environmental neurodegeneration, juvenile exposure to manganese (Mn) followed by adult infection with western equine encephalitic virus (WEEV). We found that WEEV alone produced a significant PD effect, evident by immunohistological staining of pathogenic markers and behavioral analyses; and that WEEV and Mn exposure partially enhanced this effect. These exposures were conducted in both wildtype mice and in astrocyte-specific knockout mice lacking nuclear factor Ikappa-B kinase subunit beta (IKK-KO), hypothesizing that innate immune inflammatory signaling in reactive astrocytes modulates neuroinflammation and neuronal injury following combined exposure to Mn and WEEV. In multi-hit and single exposure treatment groups, IKK-KO mice displayed reduced viral replication and had decreased α-synuclein protein aggregation, astrogliosis and neuronal loss in multiple brain regions including the substantia nigra pars compacta, suggesting that astrocyte-mediated neuroinflammation may be one mechanism by which developmental toxin exposure can potentiate vulnerability to subsequent viral infections. Given the relevance of metal toxicity and viral infection to public health, these results provide insight into disease etiology and support further exploration of neuroinflammation as a mechanism of neurodegenerative pathologies.