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Xue, Yuan Chao (Tim)

University of British Columbia

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons in the central nervous system. Emerging evidence suggests that viruses such as enterovirus (EV) might play a role during ALS pathogenesis. However, available clinical data about EV association with ALS are inconclusive, and the underlying mechanisms remain unclear. EV is a group of highly neurotropic RNA viruses that include poliovirus and non-polioviruses (e.g., coxsackievirus). Since the near eradication of poliovirus, there are emerging reports of severe neurological complications associated with non-polioviruses. The objective of this dissertation is to understand the potential role of EV in ALS pathogenesis. We recently discovered that EV infection in vitro led to ALS-like pathologies such as TDP-43 cleavage, mislocalization, and aggregation. I hypothesize that EV infection could induce and exacerbate ALS-like phenotypes through EV-induced neurotoxicity and ALS-related pathologies (e.g., TDP-43 mislocalization). To address this hypothesis, I demonstrated that infection with coxsackievirus B3 (CVB3), an EV model in this dissertation, in the brain of Balb/c mice resulted in tissue damage, immune cell infiltration, and TDP-43 mislocalization. I further showed that CVB3 infection exacerbated motor dysfunctions and reduced mouse lifespan in SOD1G85R mice (an ALS mouse model that develops progressive ALS-like phenotypes), but not in non-transgenic normal mice, suggesting that CVB3 infection is likely a risk factor but not a cause for ALS. I then discovered that early but not late treatment with ribavirin, a nucleoside analog anti-RNA viral drug, mitigated CVB3-mediated disease exacerbation in SOD1G85R mice, suggesting a potential involvement of “prion-like mechanism” independent of persistent infection in the development of ALS. Finally, I investigated possible additional mechanisms, other than TDP-43 pathology, neuroinflammation, and damage, related to EV-induced neurotoxicity and ALS-related pathology. I reported that FUS (an ALS-associated RNA-binding protein) plays an anti-viral role against CVB3 by interfering with virus translation and through promoting type I interferon and proinflammatory cytokine/chemokine gene expression. Collectively, I showed that CVB3 infection acts as a risk factor for ALS, with multiple potential contributing mechanisms. The findings under its current setup are significant because they provide first-of-its-kind in vivo evidence supporting EV as a risk factor for ALS.

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2021-12-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/80468

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/