Beckham lab discovers that alpha-synuclein, the protein that
causes Parkinson’s disease, functions as a neuron-specific restriction factor
to inhibit viral infections in the brain.
Following viral infection of neurons, alpha-synuclein
protein expression is increased in primary neuron cultures. Virus-induced
alpha-synuclein localizes with virus proteins and with the endoplasmic
reticulum (ER)-associated protein, Rab1, in neurons. In a mouse model of viral
encephalitis with West Nile virus, mice lacking the gene for alpha-synuclein
(knockout mice) are completely normal until challenged by viral infection. Upon
viral challenge, alpha-synuclein knockout mice exhibit marked increase in viral
growth, neuronal death, disease and mortality compared to control mice. Following
viral infection of knockout mice, there are no differences in interferon
responses or CD3+ Tcell responses to viral infection. However, alpha-synuclein
knockout primary neurons exhibit robust changes in endoplasmic reticulum (ER)
stress responses. Specific changes ER stress signaling are important in the
pathogenesis of viral infections in neurons and play a role in virus-induced
Thus, we conclude that alpha-synuclein functions as a novel restriction factor
in the central nervous system by localizing to virus-induced membranes and altering
ER-associated signaling and inhibiting viral growth in neurons. These data were
recently accepted for publication in the Journal of Virology (PMID: 26719256).
This work was completed by Erica Beatman, Aaron Massey and Katie Shives in the
Beckham lab. Alphavirus experiments were completed in collaboration with the
Tem Morrison laboratory and Kristina Burrack in the Department of Immunology
and Microbiology at the University of Colorado Anschutz Medical Campus.