Exploring a Role for the Parkinson Disease-Linked GBA1 Gene in Host Responses to Infections

Abstract

Typical Parkinson’s Disease (PD) is a complex disease that arises from a combination of factors including genetics, environment, gene-environment interactions, sex and age. How these factors interact has yet to be elucidated. We have previously published roles for PD-linked genes in response to microbial infections in an effort to model gene-environment interactions in PD. Mutations in the GBA1 gene, encoding a protein that confers glucocerebrosidase (GCase) activity, represent the commonest risk factor for PD development. In the present study, we sought to understand the role of murine Gba1 in microbial infection. GCase activity was found to be sex- and organ-dependent in young adult mice carrying the p.D409V mutation. Mice carrying Gba1 p.D409V knock-in mutations did not show altered immune outcomes in response to Influenza virus H1N1, bacterial Salmonella typhimurium, or serial infections of the two. In response to Vesicular Stomatitis Virus (VSV), p.D409V mice survived at a higher rate overall compared to their wild type littermates, while homozygous males survived at a higher rate compared to wild type males in a sex-dependent manner. Heterozygous females had a lower viral load in the lung after VSV infection. GCase activity was found to be altered in VSV-infected p.D409V mice in a sex-and organ-dependent manner. Taken together, this study identifies a possible role for Gba1 in host response to an acute neurotropic infection and highlights the importance of exploring sex-dependent outcomes in Gba1-focused studies.