Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain

Abstract

We have discovered that native, neuronal expression of alpha-synuclein (Asyn) inhibits viral infection, injury, and disease in the central nervous system (CNS). Enveloped RNA viruses, such as West Nile virus (WNV), invade the 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. The infectious 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 the titers in wild-type and heterozygote littermates. Asyn-knockout mice also exhibited significantly increased virusinduced mortality compared to Asyn heterozygote or homozygote control mice. Virus-induced Asyn localized to perinuclear, neuronal regions expressing viral envelope protein and the endoplasmic reticulum (ER)-associated trafficking protein Rab1. In Asyn-knockout primary neuronal cultures, the levels of expression of ER signaling pathways, known to support WNV replication, were significantly elevated before and during viral infection compared to those in Asyn-expressing primary neuronal cultures. 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 the expression of native alpha-synuclein, a protein that is closely associated with the development of Parkinson's disease. IMPORTANCENeuroinvasive viruses such as West Nile virus are able to infect neurons and cause severe disease, such as encephalitis, or 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 alphasynuclein 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 the native expression of alpha-synuclein in the CNS.

A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity

“…Recently, human αS was shown to chemo-attract rodent microglia suggesting that αS could directly promote neuro-inflammatory damage within the CNS 5 . In addition, αS has also recently been shown to be protective in mice infected with by neurotropic RNA viruses, such as West Nile Virus (WNV) and Venezuelan Equine Encephalitis 6 suggesting that it can play a beneficial role in immune defense. Based on these studies we hypothesized that αS in the ENS might play a role in the innate immune defenses of the GI tract.…”

Infectious immunity in the central nervous system and brain function

“…Although inflammation is critical for CNS pathogen clearance, lasting effects of immune molecules and pathogen by-products may represent an underlying mechanism of neurologic dysfunction. During infectious and noninfectious neurological diseases, innate immune molecules such as complement proteins and cytokines regulate synaptic plasticity and neurogenesis, whereas amyloid-β and α-synuclein, biomarkers of neurodegenerative diseases, show antimicrobial roles 141,142 . These findings suggest that, depending on the pathogen, host genotype or environmental factors, both canonical and noncanonical anti-pathogen pathways may affect interneuronal communication, leading to adaptive or maladaptive effects on brain function.…”

How does parkinson's disease begin? Perspectives on neuroanatomical pathways, prions, and histology

“…The normally soluble protein α‐syn is predominantly found in nerve terminals and may be involved interneuronal vesicle transport . Interestingly, recent studies have shown that native α‐syn may be a neuron‐specific inhibitor preventing access of neuro‐invasive viruses to the central nervous system perhaps by inhibiting viral exocytosis pathways . The α‐syn has the propensity for spontaneous misfolding and displays prion‐like properties in vitro, including cell‐to‐cell propagation .…”

“…Again, a possible interpretation is that the inflammatory state (ie, appendicitis) preceding the appendectomy increases the risk of initiating the α‐syn aggregation cascade. At the moment, this hypothesized association between gut inflammation/infection and α‐syn aggregation remains speculative, but the novel findings that native α‐syn may inhibit the access of neuro‐invasive viruses to the CNS could be involved . Such infection/α‐syn aggregation interactions could potentially be studied in the novel transgenic rodent models of PD.…”