Interaction between coxsackievirus B3 infection and α-synuclein in models of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. PD is pathologically characterized by the death of midbrain dopaminergic neurons and the accumulation of intracellular protein inclusions called Lewy bodies or Lewy neurites. The major component of Lewy bodies is α-synuclein (α-syn). Prion-like propagation of α-syn has emerged as a novel mechanism in the progression of PD. This mechanism has been investigated to reveal factors that initiate Lewy pathology with the aim of preventing further progression of PD. Here, we demonstrate that coxsackievirus B3 (CVB3) infection can induce α-syn-associated inclusion body formation in neurons which might act as a trigger for PD. The inclusion bodies contained clustered organelles, including damaged mitochondria with α-syn fibrils. α-Syn overexpression accelerated inclusion body formation and induced more concentric inclusion bodies. In CVB3-infected mice brains, α-syn aggregates were observed in the cell body of midbrain neurons. Additionally, α-syn overexpression favored CVB3 replication and related cytotoxicity. α-Syn transgenic mice had a low survival rate, enhanced CVB3 replication, and exhibited neuronal cell death, including that of dopaminergic neurons in the substantia nigra. These results may be attributed to distinct autophagy-related pathways engaged by CVB3 and α-syn. This study elucidated the mechanism of Lewy body formation and the pathogenesis of PD associated with CVB3 infection.

Author summary

Prion-like propagation of α-syn has emerged as a novel mechanism involved in the progression of Parkinson’s disease (PD). This process has been extensively investigated to identify the factors that initiate Lewy pathology to prevent further progression of PD. Nevertheless, initial triggers of Lewy body (LB) formation leading to the acceleration of the process still remain elusive. Infection is increasingly recognized as a risk factor for PD. In particular, several viruses have been reported to be associated with both acute and chronic parkinsonism. It has been proposed that peripheral infections including viral infections accompanying inflammation may trigger PD. In the present study, we explored whether coxsackievirus B3 (CVB3) interacts with α-syn to induce aggregation and further Lewy body formation, thereby acting as a trigger and whether α-syn affects the replication of coxsackievirus. It is important to identify the factors that initiate Lewy pathology to understand the pathogenesis of PD. Our findings clarify the mechanism of LB formation and the pathogenesis of PD associated with CVB3 infection.