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.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases
Initial triggers of Lewy body (LB) formation leading to the acceleration of the process still remain elusive
The mRNA levels of α-syn were decreased in dSH-SY5Y cells and primary cortical neurons infected with coxsackievirus B3 (CVB3) (Fig 1C)
Summary
PD is pathologically characterized by the death of midbrain dopaminergic neurons and the accumulation of intracellular protein inclusions termed Lewy bodies (LBs) or Lewy neurites (LNs) [1, 2]. The major component of these inclusions is α-synuclein (α-syn) [3]. Protein inclusions with α-syn aggregates have been observed in other neurodegenerative disorders, such as multiple system atrophy and dementia with Lewy bodies, which are collectively referred to as α-synucleinopathies [4]. Multiplications and missense mutations of the α-syn gene have been identified in patients with early onset familial PD [5]. Genome-wide association studies have demonstrated a strong association between α-syn gene and sporadic PD [6, 7], suggesting a major role of α-syn in the pathogenesis of PD
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