Alpha-synuclein expression restricts RNA viral infections in the brain. - PubMed - NCBI

We have discovered that native, neuronal expression of alpha-synuclein (Asyn) inhibits viral infection, injury, and disease in the central nervous system. Enveloped RNA viruses such as West Nile virus (WNV) invade the central nervous system (CNS) and cause encephalitis; yet, little is known about the innate neuron-specific inhibitors of viral infections in the CNS. Following WNV-infection of primary neurons, we found that Asyn protein expression is increased. Infectious viral titer of WNV and Venezuelan equine encephalitis virus (VEEV) TC83 in the brains of Asyn knockout mice exhibited a mean increase of 10(4.5) infectious viral particles compared to wild-type and heterozygote littermates. Asyn knockout mice also exhibited significantly increased virus-induced mortality compared to Asyn heterozygote or homozygote control mice. Viral-induced Asyn localized to perinuclear, neuronal regions expressing viral envelope protein and the ER-associated trafficking protein, Rab1. In Asyn knockout primary neuronal cultures, ER signaling pathways known to support WNV replication are significantly elevated before and during viral infection compared to neurons expressing Asyn. We propose a model in which virus-induced Asyn localizes to ER-derived membranes, modulates virus-induced ER-stress signaling, and inhibits viral replication, growth, and injury in the CNS. These data provide a novel and important functional role for native
alpha-synuclein expression, a protein that is closely associated with the development of Parkinson's disease.
IMPORTANCE: Neuroinvasive viruses such as West Nile
virus are able to infect neurons and cause severe disease such as
encephalitis, infection of brain tissue. Following viral infection in the central nervous system only select neurons are infected, implying that neurons exhibit innate resistance to viral infections. We discovered that native neuronal expression of alpha-synuclein inhibited viral infection in the central nervous system.
When the gene for alpha-synuclein was deleted, mice exhibited significantly decreased survival, markedly increased viral growth in the brain, and evidence
of increased neuron injury. Virus-induced alpha-synuclein localized to
intracellular neuron membranes, and in the absence of alpha-synuclein expression, specific endoplasmic reticulum stress signaling events were significantly
increased. We describe a new neuron-specific inhibitor of viral infections in the central nervous system. Given the importance of alpha-synuclein as a cause of
Parkinson's disease, these data also ascribe a novel functional role for native
expression of alpha-synuclein in the CNS.
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