A Role for Parkinson's-Linked LRRK2, SNCA, and GBA1 Genes in Modulating the Course of Disease Due to RNA Virus Infections

Abstract

Parkinson's disease (PD) is a complex motor neurodegenerative disorder with heterogenous disease pathology and symptomatology. We and others believe PD to be a complex disease, requiring a combination of genetic susceptibility, sex, ageing, and environmental trigger(s) for disease initiation. For over a century, viral exposures have been correlated to PD risk. In this thesis, we sought to investigate a role for three PD-linked genes, Snca, Lrrk2, and Gba1, in the host's response to virulent, microbial pathogens in mice. We also sought to explore the neuropathological consequences in the brains of adult mice that survived infections. We previously reported that endogenous expression of Snca (encoding α-synuclein) and allelic variants of Lrrk2 (both a hyper-kinase variant, p.G2019S, and a kinase-dead variant, p.D1994S) could perturb the course of illness, as measured by survival rate and viral titres in target tissues, following nasally acquired reovirus, serotype T3D, in mouse pups. To delineate the involvement of these two proteins in peripheral- vs. brain-specific immune responses, we employed a direct brain inoculation method using reovirus T3D. In this case, all mutant neonates had the same disease course as their wild-type littermates, suggesting that both α-synuclein and Lrrk2 contribute to the host response during acute reovirus T3D-induced encephalitis primarily via peripheral rather than CNS-based immune mechanisms. Next, we investigated the role of Lrrk2 in the host's response to nasally inoculated adult mice using two distinct RNA viruses: neurotropic vesicular stomatitis virus (VSV), Indiana strain, and pneumotropic influenza A virus, serotype H1N1. Intriguingly, mice carrying a homozygous Lrrk2 p.G2019S genotype had higher mortality following VSV infection -but not following H1N1 infection- with a female sex bias. Female Lrrk2 p.G2019S mice showed decreased microgliosis upon VSV infection compared to all other groups. We also investigated the commonest PD-risk gene, Gba1, in the same viral paradigms. Homozygous mutant Gba1 p.D409V mice (with associated decreased GCase activity) were relatively protected against VSV infection - but not against influenza A virus serotype H1N1 or bacterial Salmonella typhimurium infection - with a male sex bias. Taken together, we found that three PD-linked genes could alter survival rates following nasally acquired encephalitis (Snca: reovirus T3D; Gba1: VSV; Lrrk2: both viruses). Next, the second goal of this thesis was to explore downstream effects of resolved viral infections on brain health. As such, we measured neuropathology-linked biochemical changes in the brains of wild-type and Lrrk2 p.G2019S mice that survived either VSV or H1N1 infection 6 weeks after inoculation. We observed that both viruses led to a significant increase of oxidative stress, but surprisingly, had opposing effects on α-synuclein concentration: the neurotropic virus decreased it but H1N1 increased it, although the effects were not dependent on the p.G2019S mutation. Notably, we also identified a strong induction of tau phosphorylation (p-Tau) in the brain following these viral exposures. In reovirus T3D-infected neonates, the abundance of p-Tau protein was elevated during peak infection at 8 days post inoculation, when compared to mock-treated animals, with a further rise in Lrrk2 p.G2019S mutant pups. In adult mice, p-Tau remained high in VSV- or H1N1-infected brains at least until six weeks post inoculation. In summary, this thesis demonstrates a complex interplay between three PD-linked genes and viral infections in mice, showing that their loci can alter the course of illness in these infection models. We also found that viral infections, even those without neurotropism, such as H1N1, can lead to neurodegeneration-linked, biochemical changes in the brain of wild-type and mutant mice. These observations suggest that viral exposures could act as risk factors in the development of numerous neurodegenerative diseases that include tauopathies and PD.