Characterizing the Role of α-Synuclein in Innate Defenses

Abstract

Typical Parkinson’s disease (PD) is thought to be caused by a combination of genetic and environmental factors. α-Synuclein (SNCA) is central to PD pathogenesis; however, functions of SNCA outside the brain remain largely unknown. We, and others, have found that wild-type Snca expression confers anti-microbial effects in mice by reducing the severity of viral infections. Our aim is to further characterize a role of SNCA in systemic and brain health of the host during infection. We hypothesize that SNCA plays a role in innate defenses and that SNCA gene dosage will modulate outcomes of infection in the brain following pathogen exposure. Intranasal delivery of reovirus in mouse pups causes systemic illness, leading to encephalitis. In this study, intracranial inoculations of reovirus are used to differentiate the relative contribution of Snca-mediated protection in the brain versus the periphery. Two outcomes are monitored: survival and viral titres in select organs. When comparing wild-type Snca, heterozygous, and knock-out mice, I found that Snca expression did not confer any protection with respect to survival or regarding viral brain titres. These results are paralleled by cellular overexpression models. Unexpectedly, the anti-viral property of Snca, which was previously observed systemically with three distinct dsRNA viruses, did not extend to a paradigm where neural cells were directly exposed to reovirus. These results suggest a complex, anti-viral role for Snca in host defenses that may be mediated, in part, outside the central nervous system. Future studies will address whether this occurs in peripheral neurons or cells of hematopoietic lineages.